Melanocortin Receptor Ligands
20170240595 · 2017-08-24
Assignee
Inventors
Cpc classification
A61P1/04
HUMAN NECESSITIES
A61P31/00
HUMAN NECESSITIES
C07K14/665
CHEMISTRY; METALLURGY
A61P25/18
HUMAN NECESSITIES
A61P1/14
HUMAN NECESSITIES
A61P17/02
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
A61P19/06
HUMAN NECESSITIES
A61P9/02
HUMAN NECESSITIES
A61P37/06
HUMAN NECESSITIES
A61P15/00
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
A61P19/08
HUMAN NECESSITIES
A61P7/00
HUMAN NECESSITIES
A61P9/10
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
A61P15/08
HUMAN NECESSITIES
A61P7/04
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
A61P1/00
HUMAN NECESSITIES
A61P7/08
HUMAN NECESSITIES
International classification
Abstract
The present invention is directed to compounds according to formula,
(R.sup.2R.sup.3)-A.sup.1-c(A.sup.2-A.sup.3-A.sup.4-A.sup.5-A.sup.6-A.sup.7-A.sup.8-A.sup.9)-A.sup.10-R.sup.1,
and pharmaceutically-acceptable salts thereof that act as ligands for one or more of the melanocortin receptors, to methods of using such compounds to treat mammals and to pharmaceutical compositions comprising said compounds.
Claims
1. A compound according to formula (I):
(R.sup.2R.sup.3)-A.sup.1-c(A.sup.2-A.sup.3-A.sup.4-A.sup.5-A.sup.6-A.sup.7-A.sup.8-A.sup.9)-A.sup.10-R.sup.1 wherein: A.sup.1 is Acc, HN—(CH.sub.2).sub.m—C(O), L- or D-amino acid or deleted; A.sup.2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A.sup.3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid or deleted; A.sup.4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X.sup.1,X.sup.2,X.sup.3,X.sup.4,X.sup.5)Phe; A.sup.5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X.sup.1,X.sup.2,X.sup.3,X.sup.4,X.sup.5)Phe, L-Phe or D-(Et)Tyr; A.sup.6 is Arg, hArg, Dab, Dap, Lys, Orn or HN—CH((CH.sub.2).sub.n—N(R.sup.4R.sup.5))—C(O); A.sup.7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal or D-Bip; A.sup.8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN—(CH.sub.2).sub.s—C(O) or deleted; A.sup.9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys; A.sup.10 is Acc, HN—(CH.sub.2).sub.t—C(O), L- or D-amino acid or deleted; R.sup.1 is —OH or —NH.sub.2; R.sup.2 and R.sup.3 is, independently for each occurrence, H, (C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)heteroalkyl, (C.sub.1-C.sub.30)acyl, (C.sub.2-C.sub.30)alkenyl, (C.sub.2-C.sub.30)alkynyl, aryl(C.sub.1-C.sub.30)alkyl, aryl(C.sub.1-C.sub.30)acyl, substituted (C.sub.1-C.sub.30)alkyl, substituted (C.sub.1-C.sub.30)heteroalkyl, substituted (C.sub.1-C.sub.30)acyl, substituted (C.sub.2-C.sub.30)alkenyl, substituted (C.sub.2-C.sub.30)alkynyl, substituted aryl(C.sub.1-C.sub.30)alkyl or substituted aryl(C.sub.1-C.sub.30)acyl; R.sup.4 and R.sup.5 is, independently for each occurrence, H, (C.sub.1-C.sub.40)alkyl, (C.sub.1-C.sub.40)heteroalkyl, (C.sub.1-C.sub.40)acyl, (C.sub.2-C.sub.40)alkenyl, (C.sub.2-C.sub.40)alkynyl, aryl(C.sub.1-C.sub.40)alkyl, aryl(C.sub.1-C.sub.40)acyl, substituted (C.sub.1-C.sub.40)alkyl, substituted (C.sub.1-C.sub.40)heteroalkyl, substituted (C.sub.1-C.sub.40)acyl, substituted (C.sub.2-C.sub.40)alkenyl, substituted (C.sub.2-C.sub.40)alkynyl, substituted aryl(C.sub.1-C.sub.40)alkyl, substituted aryl(C.sub.1-C.sub.40)acyl, (C.sub.1-C.sub.40)alkylsulfonyl or —C(NH)—NH.sub.2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; and X.sup.1, X.sup.2, X.sup.3, X.sup.4, and X.sup.5 each is, independently for each occurrence, H, F, Cl, Br, I, (C.sub.1-10)alkyl, substituted (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl, substituted (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl, substituted (C.sub.2-10)alkynyl, aryl, substituted aryl, OH, NH.sub.2, NO.sub.2, or CN; provided that (I). when R.sup.4 is (C.sub.1-C.sub.4)acyl, aryl(C.sub.1-C.sub.40)acyl, substituted (C.sub.1-C.sub.40)acyl, substituted aryl(C.sub.1-C.sub.40)acyl, (C.sub.1-C.sub.40)alkylsulfonyl or —C(NH)—NH.sub.2, then R.sup.5 is H, (C.sub.1-C.sub.40)alkyl, (C.sub.1-C.sub.40)heteroalkyl, (C.sub.2-C.sub.40)alkenyl, (C.sub.2-C.sub.40)alkynyl, aryl(C.sub.1-C.sub.40)alkyl, substituted (C.sub.1-C.sub.40)alkyl, substituted (C.sub.1-C.sub.4)heteroalkyl, substituted (C.sub.2-C.sub.40)alkenyl, substituted (C.sub.2-C.sub.40)alkynyl or substituted aryl(C.sub.1-C.sub.40)alkyl; (II). when R.sup.2 is (C.sub.1-C.sub.30)acyl, aryl(C.sub.1-C.sub.30)acyl, substituted (C.sub.1-C.sub.30)acyl or substituted aryl(C.sub.1-C.sub.30)acyl, then R.sup.3 is H, (C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)heteroalkyl, (C.sub.2-C.sub.30)alkenyl, (C.sub.2-C.sub.30)alkynyl, aryl(C.sub.1-C.sub.30)alkyl, substituted (C.sub.1-C.sub.30)alkyl, substituted (C.sub.1-C.sub.30)heteroalkyl, substituted (C.sub.2-C.sub.30)alkenyl, substituted (C.sub.2-C.sub.30)alkynyl or substituted aryl(C.sub.1-C.sub.30)alkyl; (III). either A.sup.3 or A.sup.8 or both must be present in said compound; (IV). when A.sup.2 is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen, then A.sup.9 is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen; (V). when A.sup.2 is Asp or Glu, then A.sup.9 is Dab, Dap, Orn or Lys; (VI). when A.sup.8 is Ala or Gly, then A.sup.1 is not Nle; and (VII). when A.sup.1 is deleted, then R.sup.2 and R.sup.3 cannot both be H; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein: A.sup.1 is A6c, Gaba, Nle, Met, Phe, D-Phe, D-2-Nal, hPhe, Chg, D-Chg, Cha, hCha, hPro, hLeu, Nip, β-hMet or Oic; A.sup.2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A.sup.3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib or deleted; A.sup.4 is His; A.sup.5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal or D-(Et)Tyr; A.sup.6 is Arg or hArg; A.sup.7 is Trp, Bip, D-Trp, 1-Nal or 2-Nal; A.sup.8 is A6c, Ala, β-Ala, Gaba, Apn or Ahx; A.sup.9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen or Lys; and A.sup.10 is Thr or deleted; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2, wherein: R.sup.2 and R.sup.3 is, independently for each occurrence, H, acyl, n-propanoyl or n-butanoyl; or a pharmaceutically acceptable salt thereof.
4. A compound according claim 1, wherein: A.sup.1 is Acc, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val or deleted; A.sup.2 is Cys, D-Cys, Pen or Asp; A.sup.3 is Gly, Ala, β-Ala, Gaba, Aib, D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or deleted; A.sup.4 is His or 3-Pal; A.sup.5 is D-Phe, D-2-Nal or D-(Et)Tyr; A.sup.6 is Arg or hArg; A.sup.7 is Trp, 1-Nal, 2-Nal, Bal, Bip or D-Trp; A.sup.8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha or deleted; A.sup.9 is Cys, D-Cys, Pen or Lys; and A.sup.10 is Thr or deleted; provided that either A.sup.3 or A.sup.8 is deleted, but not both; or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 4, wherein said compound is: Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH.sub.2; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH.sub.2; Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH.sub.2; n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH.sub.2; n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH.sub.2; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D (Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH.sub.2; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Bala-Lys)-NH.sub.2; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH.sub.2; Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 5, wherein said compound is: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; or Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; or a pharmaceutically acceptable salt thereof.
7. A compound according claim 1, wherein: A.sup.1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val or deleted; A.sup.2 is Cys, Pen or Asp; A.sup.3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or deleted; A.sup.4 is His or 3-Pal; A.sup.5 is D-Phe, D-2-Nal or D-(Et)Tyr; A.sup.6 is Arg or hArg; A.sup.7 is Trp, 2-Nal, Bal, Bip or D-Trp; A.sup.8 is Gly, Ala, β-Ala, Gaba, Apn, Ahx or deleted; A.sup.9 is Cys, D-Cys, Pen or Lys; A.sup.10 is Thr or deleted; and R.sup.2 and R.sup.3 is, independently for each occurrence, H or acyl; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7, wherein said compound is: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH.sub.2; Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-3β-Ala-D-Cys)-Thr-NH.sub.2; Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH.sub.2; D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH.sub.2; Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH.sub.2; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH.sub.2; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH.sub.2; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH.sub.2; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH.sub.2; Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH.sub.2; Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH.sub.2; or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1, wherein: A.sup.1 is Arg, D-Arg, hArg or D-hArg; or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 9, wherein A.sup.2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A.sup.3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib or deleted; A.sup.4 is His; A.sup.5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal or D-(Et)Tyr; A.sup.6 is Arg or hArg; A.sup.7 is Trp, Bip, D-Trp, 1-Nal or 2-Nal; A.sup.8 is A6c, Ala, β-Ala, Gaba, Apn or Ahx; A.sup.9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen or Lys; A.sup.10 is Thr or deleted; or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 10, wherein: R.sup.2 and R.sup.3 is, independently for each occurrence, H, acyl, n-propanoyl or n-butanoyl; or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 11, wherein A.sup.2 is Cys or Asp; A.sup.3 is D-Ala or deleted; A.sup.4 is His; A.sup.5 is D-Phe or D-2-Nal; A.sup.6 is Arg; A.sup.7 is Trp; A.sup.8 is Ala, Gaba or deleted; A.sup.9 is Cys, Pen or Lys; A.sup.10 is deleted; or a pharmaceutically acceptable salt thereof.
13. A compound according to claim 12, wherein: R.sup.2 and R.sup.3 is, independently for each occurrence, H or acyl; or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 13, wherein said compound is: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH.sub.2; Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH.sub.2; or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; or pharmaceutically acceptable salts thereof.
15. A compound according to claim 14, wherein said compound is: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; or a pharmaceutically acceptable salt thereof.
16. A compound according to claim 15, wherein said compound is: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 15, wherein said compound is: Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; or a pharmaceutically acceptable salt thereof.
18. A compound according to claim 15, wherein said compound is: Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
20. A pharmaceutical composition according to claim 19, wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition according to claim 20, wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof with a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin-1 receptor, the human melanocortin-3 receptor and the human melanocortin-5 receptor.
22. A pharmaceutical composition according to claim 21, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor.
23. A pharmaceutical composition according to claim 21, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor.
24. A pharmaceutical composition according to claim 21, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor.
25. A pharmaceutical composition according to claim 21, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor.
26. A pharmaceutical composition according to claim 19 useful for treating an acute or chronic inflammatory disease or medical condition wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
27. A pharmaceutical composition according to claim 19 useful for treating a disease or medical condition with an autoimmune component wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
28. A pharmaceutical composition according to claim 19 useful for treating a metabolic disease or medical condition accompanied by weight gain wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
29. A pharmaceutical composition according to claim 28, wherein obesity is treated.
30. A pharmaceutical composition according to claim 28, wherein a feeding disorder is treated.
31. A pharmaceutical composition according to claim 19 useful for decreasing food intake.
32. A pharmaceutical composition according to claim 19 useful for decreasing body weight.
33. A pharmaceutical composition according to claim 19 useful for decreasing food intake and decreasing body weight.
34. A pharmaceutical composition according to claim 31 useful for decreasing food intake wherein said compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition according to claim 34 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition according to claim 34 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
37. A pharmaceutical composition according to claim 34 useful for decreasing food intake wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
38. A pharmaceutical composition according to claim 32 useful for decreasing body weight wherein said compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
39. A pharmaceutical composition according to claim 38 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
40. A pharmaceutical composition according to claim 38 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition according to claim 38 useful for decreasing food intake wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
42. A pharmaceutical composition according to claim 33 useful for decreasing food intake and decreasing body weight wherein said compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
43. A pharmaceutical composition according to claim 42 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
44. A pharmaceutical composition according to claim 42 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
45. A pharmaceutical composition according to claim 42 useful for decreasing food intake wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
46. A pharmaceutical composition according to claim 19 useful for treating a metabolic disease or medical condition accompanied by weight loss wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
47. A pharmaceutical composition according to claim 46 useful for treating anorexia.
48. A pharmaceutical composition according to claim 46 useful for treating bulimia.
49. A pharmaceutical composition according to claim 46 useful for treating AIDS wasting or wasting in frail elderly.
50. A pharmaceutical composition according to claim 46 useful for treating cachexia or cancer cachexia.
51. A pharmaceutical composition according to claim 19 useful for treating a neoplastic disease or medical condition wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
52. A pharmaceutical composition according to claim 19 useful for treating a reproductive or sexual medical condition wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
53. A pharmaceutical composition according to claim 19 useful for treating a disease or medical condition resulting from treatment or insult to an organism wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
54. A pharmaceutical composition according to claim 19 useful for treating a cardiovascular disease or medical condition wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
55. A pharmaceutical composition according to claim 19 useful for treating a pulmonary disease or medical condition wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
56. A pharmaceutical composition according to claim 19 useful for treating a disease or medical condition wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
57. A pharmaceutical composition according to claim 19 useful for treating a dermatological disease or medical condition wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
58. A pharmaceutical composition according to claim 19 useful for treating a behavioral or central nervous system or neuronal disease or medical condition wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
59. A pharmaceutical composition according to claim 19 useful for treating a renal disease or medical condition wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
60. A pharmaceutical composition according to claim 19 useful for modulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth.
61. A pharmaceutical composition according to claim 19 useful for modulating bone metabolism, bone formation and bone development.
62. A pharmaceutical composition according to claim 19 useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or for treating alcohol abuse.
63. A pharmaceutical composition according to claim 62 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
64. A pharmaceutical composition according to claim 62 useful for reducing alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
65. A pharmaceutical composition according to claim 62 useful for treating alcoholism wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
66. A pharmaceutical composition according to claim 62 useful for treating alcohol abuse wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
67. A pharmaceutical composition according to claim 63 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
68. A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
69. A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
70. A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
71. A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
72. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to inhibit alcohol consumption in a subject in need of such treatment.
73. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist of according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to reduce alcohol consumption in a subject in need of such treatment.
74. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcoholism in a subject in need of such treatment.
75. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcohol abuse in a subject in need of such treatment.
76. A method of eliciting an agonist or antagonist effect from a melanocortin receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.
77. A method according to claim 76, wherein said compound is a selective melanocortin 4 receptor agonist.
78. A method according to claim 77, wherein said compound is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
79. A method according to claim 78, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
80. A method according to claim 78, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
81. A method according to claim 78, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
82. A method according to claim 78, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
83. A method of treating an acute or chronic inflammatory disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
84. A method of treating a disease or medical condition with an autoimmune component by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
85. A method of treating a metabolic disease or medical condition accompanied by weight gain by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
86. A method according to claim 85, wherein obesity is treated.
87. A method according to claim 85, wherein a feeding disorder is treated.
88. A method of decreasing food intake according to claim 76.
89. A method of decreasing body weight according to claim 76.
90. A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76.
91. A method of decreasing food intake by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 88 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
92. A method according to claim 91, wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
93. A method according to claim 91, wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
94. A method according to claim 91, wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
95. A method of decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 89 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
96. A method according to claim 95, wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
97. A method according to claim 95, wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
98. A method according to claim 95, wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
99. A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 90 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
100. A method according to claim 99, wherein said compound is 22493 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
101. A method according to claim 99, wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
102. A method according to claim 99, wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2, or a pharmaceutically acceptable salt thereof.
103. A method of treating a metabolic disease or medical condition accompanied by weight loss by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
104. A method according to claim 103, wherein anorexia is treated.
105. A method according to claim 103, wherein bulimia is treated.
106. A method according to claim 103, wherein AIDS wasting or wasting in frail elderly is treated.
107. A method according to claim 103, wherein cachexia or cancer cachexia is treated.
108. A method of treating a neoplastic disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
109. A method of treating a reproductive or sexual medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
110. A method of treating a disease or medical condition resulting from treatment or insult to an organism by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
111. A method of treating a cardiovascular disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
112. A method of treating a pulmonary disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
113. A method of treating a disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
114. A method of treating a dermatological disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
115. A method of treating a behavioral or central nervous system or neuronal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
116. A method of treating a renal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76, wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
117. A method of modulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76.
118. A method of modulating bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76.
119. A method of inhibiting alcohol consumption, reducing alcohol consumption, treating alcoholism, or treating alcohol abuse by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76.
120. A method of inhibiting alcohol consumption according to claim 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
121. A method of reducing alcohol consumption according to claim 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
122. A method of treating alcoholism according to claim 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
123. A method of treating alcohol abuse according to claim 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
124. A method of inhibiting alcohol consumption according to claim 120, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
125. A method according to claim 124, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
126. A method according to claim 124, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
127. A method according to claim 124, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
128. A method according to claim 124, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
129. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat a disease or condition selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders, Prader-Willi Syndrome, a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, skin cancer, endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, decreased sexual response in females, organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, enhanced immune tolerance, allergies, psoriasis, skin pigmentation depletion, acne, keloid formation, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.
130. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to modulate ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection, nerve growth, bone metabolism, bone formation and bone development.
131. A compound according to formula II:
(R.sup.2R.sup.3)-A.sup.1-c(A.sup.2-A.sup.3-A.sup.4-A.sup.5-A.sup.6-A.sup.7-A.sup.8-A.sup.9)-NH.sub.2 wherein: A.sup.1 is Nle or deleted; A.sup.2 is Cys or Asp; A.sup.3 is Glu or D-Ala; A.sup.4 is His; A.sup.5 is D-Phe; A.sup.6 is Arg; A.sup.7 is Trp, 2-Nal or Bal; A.sup.8 is Gly, Ala, D-Ala, β-Ala, Gaba or Apn; A.sup.9 is Cys or Lys; each of R.sup.2 and R.sup.3 is independently selected from the group consisting of H or (C.sub.1-C.sub.6)acyl; provided that (I). when R.sup.2 is (C.sub.1-C.sub.6)acyl, then R.sup.3 is H; and (II). when A.sup.2 is Cys, then A.sup.9 is Cys, or a pharmaceutically acceptable salt thereof.
132. A compound according to claim 131, wherein said compound is: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH.sub.2; Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH.sub.2; Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH.sub.2; Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH.sub.2; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; or Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH.sub.2; or a pharmaceutically acceptable salt thereof.
133. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
134. A pharmaceutical composition according to claim 133, wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof.
135. A pharmaceutical composition according to claim 134, wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
136. A pharmaceutical composition according to claim 135, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
137. A pharmaceutical composition according to claim 135, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
138. A pharmaceutical composition according to claim 135, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
139. A pharmaceutical composition according to claim 135, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
140. A pharmaceutical composition according to claim 133 useful for treating an acute or chronic inflammatory disease or medical condition wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
141. A pharmaceutical composition according to claim 133 useful for treating a disease or medical condition with an autoimmune component wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
142. A pharmaceutical composition according to claim 133 useful for treating a metabolic disease or medical condition accompanied by weight gain wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
143. A pharmaceutical composition according to claim 142, wherein obesity is treated.
144. A pharmaceutical composition according to claim 142, wherein a feeding disorder is treated.
145. A pharmaceutical composition according to claim 133 useful for decreasing food intake.
146. A pharmaceutical composition according to claim 133 useful for decreasing body weight.
147. A pharmaceutical composition according to claim 133 useful for decreasing food intake and decreasing body weight.
148. A pharmaceutical composition according to claim 133 useful for treating a metabolic disease or medical condition accompanied by weight loss wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
149. A pharmaceutical composition according to claim 148 useful for treating anorexia.
150. A pharmaceutical composition according to claim 148 useful for treating bulimia.
151. A pharmaceutical composition according to claim 148 useful for treating AIDS wasting or wasting in frail elderly.
152. A pharmaceutical composition according to claim 148 useful for treating cachexia or cancer cachexia.
153. A pharmaceutical composition according to claim 133 useful for treating a neoplastic disease or medical condition wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
154. A pharmaceutical composition according to claim 133 useful for treating a reproductive or sexual medical condition wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
155. A pharmaceutical composition according to claim 133 useful for treating a disease or medical condition resulting from treatment or insult to an organism wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
156. A pharmaceutical composition according to claim 133 useful for treating a cardiovascular disease or medical condition wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
157. A pharmaceutical composition according to claim 133 useful for treating a pulmonary disease or medical condition wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
158. A pharmaceutical composition according to claim 133 useful for treating a disease or medical condition wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
159. A pharmaceutical composition according to claim 133 useful for treating a dermatological disease or medical condition wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
160. A pharmaceutical composition according to claim 133 useful for treating a behavioral or central nervous system or neuronal disease or medical condition wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
161. A pharmaceutical composition according to claim 133 useful for treating a renal disease or medical condition wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
162. A pharmaceutical composition according to claim 133 useful for modulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth.
163. A pharmaceutical composition according to claim 133 useful for modulating bone metabolism, bone formation and bone development.
164. A pharmaceutical composition according to claim 133 useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or for treating alcohol abuse.
165. A pharmaceutical composition according to claim 164 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
166. A pharmaceutical composition according to claim 164 useful for reducing alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
167. A pharmaceutical composition according to claim 164 useful for treating alcoholism wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
168. A pharmaceutical composition according to claim 164 useful for treating alcohol abuse wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
169. A pharmaceutical composition according to claim 165 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
170. A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
171. A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
172. A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
173. A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
174. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to inhibit alcohol consumption in a subject in need of such treatment.
175. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist of according to any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to reduce alcohol consumption in a subject in need of such treatment.
176. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcoholism in a subject in need of such treatment.
177. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to c any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcohol abuse in a subject in need of such treatment.
178. A method of eliciting an agonist or antagonist effect from a melanocortin receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof.
179. A method according to claim 178, wherein said compound is a selective melanocortin 4 receptor agonist.
180. A method according to claim 179, wherein said compound is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
181. A method according to claim 180, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
182. A method according to claim 180, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
183. A method according to claim 180, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
184. A method according to claim 180, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
185. A method of treating an acute or chronic inflammatory disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
186. A method of treating a disease or medical condition with an autoimmune component by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
187. A method of treating a metabolic disease or medical condition accompanied by weight gain by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
188. A method according to claim 187, wherein obesity is treated.
189. A method according to claim 187 wherein a feeding disorder is treated.
190. A method of decreasing food intake according to claim 178.
191. A method of decreasing body weight according to claim 178.
192. A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178.
193. A method of treating a metabolic disease or medical condition accompanied by weight loss by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
194. A method according to claim 193, wherein anorexia is treated.
195. A method according to claim 193, wherein bulimia is treated.
196. A method according to claim 193, wherein AIDS wasting or wasting in frail elderly is treated.
197. A method according to claim 193, wherein cachexia or cancer cachexia is treated.
198. A method of treating a neoplastic disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
199. A method of treating a reproductive or sexual medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
200. A method of treating a disease or medical condition resulting from treatment or insult to an organism by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
201. A method of treating a cardiovascular disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
202. A method of treating a pulmonary disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
203. A method of treating a disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
204. A method of treating a dermatological disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
205. A method of treating a behavioral or central nervous system or neuronal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
206. A method of treating a renal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178, wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
207. A method of modulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178.
208. A method of modulating bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178.
209. A method of inhibiting alcohol consumption, reducing alcohol consumption, treating alcoholism, or treating alcohol abuse by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178.
210. A method of inhibiting alcohol consumption according to claim 209, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
211. A method of reducing alcohol consumption according to claim 209, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
212. A method of treating alcoholism according to claim 209, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
213. A method of treating alcohol abuse according to claim 209, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
214. A method of inhibiting alcohol consumption according to claim 210, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC.sub.50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
215. A method according to claim 214, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
216. A method according to claim 214, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
217. A method according to claim 214, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
218. A method according to claim 214, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC.sub.50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
219. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat a disease or condition selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders, Prader-Willi Syndrome, a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, skin cancer, endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, decreased sexual response in females, organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, enhanced immune tolerance, allergies, psoriasis, skin pigmentation depletion, acne, keloid formation, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.
220. The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claim 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to modulate ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection, nerve growth, bone metabolism, bone formation and bone development.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0411]
[0412]
[0413]
[0414]
[0415]
[0416]
[0417]
[0418]
DETAILED DESCRIPTION OF THE INVENTION
[0419] The nomenclature used to define the peptides is that typically used in the art wherein the amino group at the N-terminus appears to the left and the carboxyl group at the C-terminus appears to the right. Where the amino acid has isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents and other references mentioned herein are incorporated by reference.
NOMENCLATURE AND ABBREVIATIONS
[0420]
TABLE-US-00001 Symbol Meaning Abu α-aminobutyric acid Ac acyl group Acc 1-amino-1-cyclo(C.sub.3-C.sub.9)alkyl carboxylic acid A3c 1-amino-1-cyclopropanecarboxylic acid A4c 1-amino-1-cyclobutanecarboxylic acid A5c 1-amino-1-cyclopentanecarboxylic acid A6c 1-amino-1-cyclohexanecarboxylic acid Aha 7-aminoheptanoic acid Ahx 6-aminohexanoic acid Aib α-aminoisobutyric acid Ala or A alanine β-Ala β-alanine Apn 5-aminopentanoic acid (HN—(CH2).sub.4—C(O) Arg or R arginine hArg homoarginine Asn or N asparagine Asp or D aspartic acid Bal 3-benzothienylalanine Bip 4,4′-biphenylalanine, represented by the structure
[0421] Certain other abbreviations used herein are defined as follows: [0422] Boc: tert-butyloxycarbonyl [0423] Bzl: benzyl [0424] DCM: dichloromethane [0425] DIC: N, N-diisopropylcarbodiimide [0426] DIEA: diisopropylethyl amine [0427] Dmab: 4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)amino}benzyl [0428] DMAP: 4-(dimethylamino)pyridine [0429] DMF dimethylformamide [0430] DNP: 2,4-dinitrophenyl [0431] Fm: fluorenylmethyl [0432] Fmoc: fluorenylmethyloxycarbonyl [0433] For: formyl [0434] HBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate [0435] cHex cyclohexyl [0436] HOAT: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate [0437] HOBt: 1-hydroxy-benzotriazole [0438] MBHA 4-methylbenzhydrylamine [0439] Mmt: 4-methoxytrityl [0440] NMP: N-methylpyrrolidone [0441] O-tBu oxy-tert-butyl [0442] Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl [0443] PyBroP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate [0444] tBu: tert-butyl [0445] TIS: triisopropylsilane [0446] TOS: tosyl [0447] Trt trityl [0448] TFA: trifluoro acetic acid [0449] TFFH: tetramethylfluoroforamidinium hexafluorophosphate [0450] Z: benzyloxycarbonyl
[0451] Unless otherwise indicated, with the exception of the N-terminal amino acid, all abbreviations (e.g. Ala) of amino acids in this disclosure stand for the structure of —NH—C(R)(R′)—CO—, wherein R and R′ each is, independently, hydrogen or the side chain of an amino acid (e.g., R=CH.sub.3 and R′=H for Ala), or R and R′ may be joined to form a ring system.
[0452] For the N-terminal amino acid, the abbreviation stands for the structure of:
##STR00004##
[0453] The designation “NH.sub.2” in e.g., Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2, indicates that the C-terminus of the peptide is amidated. Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys), or alternatively Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH, indicates that the C-terminus is the free acid.
[0454] “-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” denotes the structure:
##STR00005##
[0455] “-c(Cys-Pen)-” or “-cyclo(Cys-Pen)-” denotes the structure:
##STR00006##
[0456] “-c(Asp-Lys)-” or “-cyclo(Asp-Lys)-” denotes the structure:
##STR00007##
[0457] “Acyl” refers to R″—C(O)—, where R″ is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alklyaryl, and is indicated in the general formula of a particular embodiment as “Ac”.
[0458] “Alkyl” refers to a hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds. The alkyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.
[0459] “Hydroxyalkyl” refers to an alkyl group wherein one or more hydrogen atoms of the hydrocarbon group are substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.
[0460] “Substituted alkyl” refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH.sub.2, —NHCH.sub.3, —NO.sub.2, and —C.sub.1-20 alkyl, wherein said —C.sub.1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, —CF.sub.3, —OCH.sub.3, —OCF.sub.3, and —(CH.sub.2).sub.0-20—COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of —(CH.sub.2).sub.0-20—COOH results in the production of an alkyl acid. Non-limiting examples of alkyl acids containing, or consisting of, —(CH.sub.2).sub.0-20—COOH include 2-norbornane acetic acid, tert-butyric acid, 3-cyclopentyl propionic acid, and the like.
[0461] The term “halo” encompasses fluoro, chloro, bromo and iodo.
[0462] “Heteroalkyl” refers to an alkyl wherein one of more of the carbon atoms in the hydrocarbon group is replaced with one or more of the following groups: amino, amido, —O—, —S— or carbonyl. In different embodiments 1 or 2 heteroatoms are present.
[0463] “Substituted heteroalkyl” refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH.sub.2, —NHCH.sub.3, —NO.sub.2, and —C.sub.1-20 alkyl, wherein said —C.sub.1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, —CF.sub.3, —OCH.sub.3, —OCF.sub.3, and —(CH.sub.2).sub.0-20—COOH. In different embodiments 1, 2, 3 or 4 substituents are present.
[0464] “Alkenyl” refers to a hydrocarbon group made up of two or more carbons where one or more carbon-carbon double bonds are present. The alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.
[0465] “Substituted alkenyl” refers to an alkenyl wherein one or more hydrogens are replaced with one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH.sub.2, —NHCH.sub.3, —NO.sub.2, and —C.sub.1-20 alkyl, wherein said —C.sub.1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, —CF.sub.3, —OCH.sub.3, —OCF.sub.3, and —(CH.sub.2).sub.0-20—COOH. In different embodiments 1, 2, 3 or 4 substituents are present.
[0466] “Aryl” refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to three conjugated or fused ring systems. Aryl includes carbocylic aryl, heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5- or 6-membered ring. Preferred atoms for a heterocyclic aryl are one or more sulfur, oxygen, and/or nitrogen. Non-limiting examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, and the like. Aryl substituents are selected from the group consisting of —C.sub.1-20 alkyl, —C.sub.1-20 alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH.sub.2, —NO.sub.2, —C.sub.1-20 alkyl substituted with halogens, —CF.sub.3, —OCF.sub.3, and —(CH.sub.2).sub.0-20—COOH. In different embodiments the aryl contains 0, 1, 2, 3, or 4 substituents.
[0467] “Alkylaryl” refers to an “alkyl” joined to an “aryl”.
[0468] The term “(C.sub.1-C.sub.12)hydrocarbon moiety” encompasses alkyl, alkenyl and alkynyl and in the case of alkenyl and alkynyl there is C.sub.2-C.sub.12.
[0469] As used herein, the term “normalizing” functions or activities refers to those types of functions which may be considered to be involved in normal body function or homeostasis of an organism. Such functions include but are not limited to activities and functions affecting body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels and the like.
[0470] As used herein, compounds which are considered to be “selective” for a particular melanocortin receptor are those compounds with a functional activity characterized by an EC.sub.50 at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 17-fold, at least about 90-fold, at least about 200-fold, at least about 3000-fold or at least about 10,000-fold, or even greater, selectivity for any melanocortin receptor as compared to any other melanocortin receptor. For example, a selective melanocortin 4 receptor agonist of the invention exhibits a functional activity characterized by an EC.sub.50 at least about 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor. Also for example, a selective melanocortin 4 receptor agonist of the invention exhibits a functional activity characterized by an EC.sub.50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
Synthesis
[0471] The peptides of this invention can be prepared by standard solid phase peptide synthesis. See, e.g., Stewart, J. M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R.sup.2 and R.sup.3 of the above generic formula may be attached to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, e.g., (C.sub.1-C.sub.30)alkyl, may be attached using reductive alkylation. Hydroxyalkyl groups, e.g., (C.sub.1-C.sub.30)hydroxyalkyl, may also be attached using reductive alkylation wherein the free hydroxyl group is protected with a t-butyl ester. Acyl groups, e.g., COE.sup.1, may be attached by coupling the free acid, e.g., E.sup.1COOH, to the free amine of the N-terminal amino acid by mixing the completed resin with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for one hour. If the free acid contains a free hydroxyl group, e.g., p-hydroxyphenylpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBt.
[0472] When R.sup.1 is —NH.sub.2, the synthesis of the peptide starts with an Fmoc-amino acid which is coupled to the Rink Amide MBHA resin. If R.sup.1 is —OH, the synthesis of the peptide starts with a Fmoc-amino acid which is coupled to Wang resin.
[0473] In the synthesis of a peptide of this invention containing A6c and/or Aib, the coupling time is 2 hours for these residues and the residue immediately following them.
[0474] The following examples describe synthetic methods for making a peptide of this invention, which methods are well-known to those skilled in the art. Other methods are also known to those skilled in the art. The examples are provided for the purpose of illustration and are not meant to limit the scope of the present invention in any manner.
Examples
Example 1: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.SUB.2
[0475] The title peptide was synthesized on an Advanced ChemTech model 396® multiple peptide synthesizer (Louisville, Ky. 40228) using Fluorenylmethyloxycarbonyl (Fmoc) chemistry. A Rink Amide 4-methylbenzylhydrylamine (MBHA) resin (Novabiochem®, San Diego, Calif.) with substitution of 0.58 mmol/g was used. The Fmoc amino acids (Novabiochem®, CA and Chem-Impex®, IL) used were Fmoc-Nle-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Ala-OH, Fmoc-His(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-Arg(Pbf)-OH, and Fmoc-Trp(Boc)-OH. The synthesis was carried out on a 0.035 mmol scale. The Fmoc groups were removed by treatment with 25% piperidine in N,N-dimethylformamide (DMF) for 30 minutes. In each coupling step, the Fmoc amino acid (10 eq, 0.35 mmol), N, N-diisopropylcarbodiimide (DIC) (10 eq, 0.35 mmol), and 1-hydroxy-benzotriazole (HOBt) (10 eq, 0.35 mmol) were used in DMF (1.4 mL). After washing with DMF, double-coupling was performed with the Fmoc-amino acid (10 eq, 0.35 mmol), 2-(1-H-benzotriazole-1-yl)-1,1,2,3-tetramethyluronium hexafluorophosphate (HBTU) (8 eq, 0.28 mmol), HOBT (10 eq, 0.35 mmol), and diisopropylethyl amine (DIEA) (20 eq, 0.7 mmol) in DMF (1.26 mL). The ACT 396® multiple peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with DMF, (2) removing Fmoc protecting group with 25% piperidine in DMF for 30 minutes, β) washing with DMF, (4) coupling with Fmoc amino acid in the presence of DIC and HOBT for 1 hour, (5) washing with DMF, (6) double-coupling with the same Fmoc amino acid in step 4 in the presence of HBTU, HOBt, and DIEA for 1 hour. The resin was coupled successively according to the sequence of the title peptide. After the peptide chain was assembled and the last Fmoc-protecting group was removed, the resin was washed completely by using DMF and dichloromethane (DCM).
[0476] To cleave the title peptide, the resin was treated with a solution (1.5 mL) of TFA, H.sub.2O and triisopropylsilane (TIS) (v/v/v: 90/6.2/3.8) for 2 hours at room temperature. The resin was filtered off and the filtrate was poured into 30 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in water (˜7 mL) and the pH of the aqueous solution was adjusted to −7.5 by adding 2N NH.sub.4HCO.sub.3. The solution was opened to the air for 72 hours at room temperature. The resulting crude product was purified on a reverse-phase preparative HPLC system with a column (4×43 cm) of C.sub.18 DYNAMAX-100® A.sup.0 (Varian®, Walnut Creek, Calif.). The column was eluted over approximately 1 hour using a linear gradient of 85% A:15% B to 30% A:70% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 10.3 mg (27% yield) of a white solid. Purity was assayed using HPLC and found to be approximately 88%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 1073.6 (in agreement with the calculated molecular weight of 1074.3).
Example 2: Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.SUB.2
[0477] The title peptide was synthesized on an Applied Biosystems® (Foster City, Calif.) model 430A peptide synthesizer which was modified to do accelerated Boc-chemistry solid phase peptide synthesis. See Schnolzer, et al., Int. J. Peptide Protein Res., 40:180 (1992). 4-methylbenzhydrylamine (MBHA) resin (Peninsula®, Belmont, Calif.) with the substitution of 0.91 mmol/g was used. The Boc amino acids (Novabiochem®, San Diego, Calif. and Chem-Impex®, Wood Dale, Ill.) used were: Boc-Cha-OH, Boc-Asp(OFm)-OH, Boc-His(DNP)-OH, Boc-D-Phe-OH, Boc-Arg(Tos)-OH, Boc-Trp(For)-OH, Boc-Gaba-OH, and Boc-Lys(Fmoc)-OH. The synthesis was carried out on a 0.20 mmol scale. The Boc groups were removed by treatment with 100% TFA for 2×1 minute. Boc amino acids (2.5 mmol) were pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF and were coupled without prior neutralization of the peptide-resin TFA salt. Coupling times were 5 minutes.
[0478] At the end of the assembly of Boc-Asp(OFm)-His(DNP)-D-Phe-Arg(Tos)-Trp(For)-Gaba-Lys(Fmoc)-MBHA, the peptide-resin was transferred into a reaction vessel on a shaker. The resin was treated twice with 25% piperidine in DMF for 15 minutes per session, washed with DMF, and shaken with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (6 eq, 0.3 mmol), DIEA (1 mL), and 4-(dimethylamino)pyridine (DMAP) (24 mg) in DMF (2 mL) for 12 hours. After washing with DMF, the resin was treated twice with 100% TFA for 2 minutes per treatment, washed with DMF and DCM, and then dried under reduced pressure. One fourth of the peptide-resin (0.05 mmol) was used for the next coupling with Boc-Cha-OH (10 eq, 0.5 mmol) in the presence of HBTU (9 eq, 0.45 mmol) and DIEA (0.25 mL) in DMF for 10 minutes. After the deprotection with 100% TFA in two sessions lasting approximately 2 minutes each, the peptide-resin was then washed with DMF. The final capping step was done by shaking the resin with acetic anhydride (40 eq, 2.0 mmol) and DIEA (20 eq, 1.0 mmol) in DMF for 1 hour. After washing with DMF, the resin was treated twice with a solution of 20% mercaptoethanol/10% DIEA in DMF, each treatment lasting approximately 30 minutes, to remove the DNP group on the Histidine side chain. The formyl group on the side chain of Tryptophan was removed by shaking with a solution of 15% ethanolamine/15% water/70% DMF twice for 30 minutes per shaking. The peptide-resin was washed with DMF and DCM and dried under reduced pressure. The final cleavage was done by stirring the peptide-resin in 10 mL of HF containing 1 mL of anisole and dithiothreitol (30 mg) at 0° C. for 75 minutes. HF was removed by a flow of nitrogen. The residue was washed with ether (6×10 mL) and extracted with 4N HOAc (6×10 mL).
[0479] The peptide mixture in the aqueous extract was purified on reverse-phase preparative high pressure liquid chromatography (HPLC) using a reverse phase VYDAC® C.sub.18 column (Nest Group®, Southborough, Mass.). The column was eluted with a linear gradient (10% to 50% of solution B over 40 minutes) at a flow rate of 10 mL/minute (Solution A=water containing 0.1% TFA; Solution B=acetonitrile containing 0.1% of TFA). Fractions were collected and checked on analytical HPLC. Those containing pure product were combined and lyophilized to dryness. 5.1 mg of a white solid was obtained. Yield was 8.9%. Purity was 94.5% based on analytical HPLC analysis. Electro-spray mass spectrometer (MS(ES))S analysis gave the molecular weight at 1148.5 (in agreement with the calculated molecular weight of 1148.3).
[0480] Other peptides of the invention can be prepared by a person of ordinary skill in the art using synthetic procedures analogous to those disclosed generally hereinabove and/or to those disclosed specifically in the foregoing examples, as were the compounds depicted in Tables 1A and 1B.
[0481] Other peptides of the invention can be prepared by a person of ordinary skill in the art using synthetic procedures analogous to those disclosed generally hereinabove and/or to those disclosed specifically in the foregoing examples, as were the compounds depicted in Tables 1A and 1B.
[0482] The following examples can be made according to the appropriate procedures described above: [0483] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH.sub.2; [0484] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH.sub.2; [0485] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH.sub.2; [0486] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH.sub.2; [0487] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; [0488] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH.sub.2; [0489] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; [0490] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH.sub.2; [0491] Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0492] Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0493] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0494] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0495] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0496] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0497] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0498] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0499] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0500] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0501] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0502] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0503] Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0504] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0505] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0506] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0507] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0508] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0509] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0510] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0511] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0512] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0513] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH.sub.2; [0514] Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0515] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0516] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0517] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0518] Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0519] Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0520] Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0521] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0522] Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0523] Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0524] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0525] n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0526] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0527] Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0528] Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH.sub.2; [0529] Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; [0530] Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; [0531] Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; [0532] Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; [0533] Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH.sub.2; [0534] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH.sub.2; [0535] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH.sub.2; [0536] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH.sub.2; [0537] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH.sub.2; [0538] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH.sub.2; [0539] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH.sub.2; [0540] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH.sub.2; [0541] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH.sub.2; [0542] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH.sub.2; [0543] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH.sub.2; [0544] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; [0545] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH.sub.2; [0546] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH.sub.2; [0547] n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH.sub.2; [0548] n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0549] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH.sub.2; [0550] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH.sub.2; [0551] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH.sub.2; [0552] Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0553] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH.sub.2; [0554] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH.sub.2; [0555] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0556] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; [0557] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; [0558] D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; [0559] D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; [0560] D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; [0561] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2; [0562] D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; [0563] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH.sub.2; [0564] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH.sub.2; [0565] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH.sub.2; [0566] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH.sub.2; [0567] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0568] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; [0569] Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH.sub.2; [0570] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH.sub.2; [0571] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH.sub.2; [0572] Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH.sub.2; [0573] Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH.sub.2; [0574] Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH.sub.2; [0575] Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH.sub.2; [0576] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH.sub.2; [0577] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH.sub.2; [0578] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0579] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; [0580] Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0581] Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0582] Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0583] Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0584] Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0585] Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0586] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0587] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; [0588] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; [0589] Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0590] Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0591] Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0592] Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0593] Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0594] Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0595] Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0596] Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0597] Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH.sub.2; [0598] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; [0599] Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH.sub.2; [0600] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH.sub.2; [0601] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH.sub.2; [0602] Ac-Nle-c(Asp-His-D-2-Na-Arg-Trp-β-Ala-Lys)-NH.sub.2; [0603] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH.sub.2; [0604] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH.sub.2; [0605] Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH.sub.2; [0606] Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH.sub.2; [0607] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH; [0608] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; [0609] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; [0610] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH; [0611] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; [0612] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; [0613] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; [0614] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; [0615] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; [0616] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; [0617] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; [0618] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; [0619] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; [0620] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; [0621] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; [0622] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; [0623] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; [0624] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; [0625] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; [0626] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; [0627] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; [0628] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH; [0629] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; [0630] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; [0631] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; [0632] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0633] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2; [0634] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; [0635] Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; [0636] Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2; [0637] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2; [0638] Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH.sub.2; [0639] Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH.sub.2; [0640] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH.sub.2; and Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH.
[0641] Other peptides of the invention can be prepared by a person of ordinary skill in the art using synthetic procedures analogous to those disclosed generally hereinabove and/or to those disclosed specifically in the foregoing examples, as were the compounds depicted in Tables 1A and 1B.
TABLES 1A and 1B—Molecular Weight and Purity for Selected Embodiments
[0642]
TABLE-US-00002 TABLE 1A Calculated Experimental Molecular Molecular Compound Weight Weight Purity Ac-Nle-c(Asp-His-D-Phe-Arg- 1095.27 1095.2 96.4 Trp-β-Ala-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg- 1149.36 1149.05 96 Trp-A6c-Lys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg- 1116.38 1115.8 98 Trp-Ahx-Cys)-NH.sub.2 D-Phe-c(Cys-His-D-Phe-Arg-Trp- 1167.38 1167.3 99 Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-Phe-Arg-Trp- 1167.38 1167.5 93 β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-Phe-Arg-Trp- 1181.41 1181.9 99 Gaba-D-Cys)-Thr-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg- 1102.35 1103 99 Trp-Apn-Cys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg- 1123.32 1123.9 99 Trp-Apn-Lys)-NH.sub.2 Ac-A6c-c(Asp-His-D-Phe-Arg- 1121.31 1121.2 93 Trp-Gaba-Lys)-NH.sub.2 Ac-D-2-Nal-c(Asp-His-D-Phe- 1193.37 1193.2 92.6 Arg-Trp-Gaba-Lys)-NH.sub.2 Ac-Cha-c(Asp-His-D-Phe-Arg- 1149.36 1149.4 94.5 Trp-Gaba-Lys)-NH.sub.2; Ac-Nle-c(Asp-His-D-Phe-Arg- 1109.3 1109.2 91.5 Trp-Gaba-Lys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1074.3 1074.6 98.3 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-β-Ala-His-D-Phe- 1074.3 1074.4 91 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-Gaba-His-D-Phe- 1088.32 1088.4 93 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-Aib-His-D-Phe- 1088.32 1088.4 80 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-Gly-His-D-Phe- 1060.27 1060.4 90 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-Ala-His-D-Phe- 1074.3 1074.4 93 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-D-Ala-His-D- 1074.3 1074.4 81 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-β-Ala-His-D- 1074.3 1074.4 92 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-Gaba-His-D-Phe- 1088.32 1088.4 94 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-Aib-His-D-Phe- 1088.32 1088.4 91 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-Gly-His-D-Phe- 1060.27 1060.4 96 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1074.3 1074.4 66 Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(Cys-β-Ala-His-D-Phe- 1074.3 1074.2 94 Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(Cys-Gaba-His-D-Phe- 1088.32 1088.2 93 Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(Cys-Aib-His-D-Phe- 1088.32 1088.4 90 Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(Cys-Gly-His-D-Phe- 1060.27 1060.4 91 Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-Ala-His-D-Phe- 1074.3 1074.4 65 Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-D-Ala-His-D- 1074.3 1074.2 93 Phe-Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-β-Ala-His-D- 1074.3 1074.4 92 Phe-Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-Gaba-His-D-Phe- 1088.32 1088.4 90 Arg-Trp-D-Cys)-NH.sub.2 Ac-Nle-c(D-Cys-Aib-His-D-Phe- 1088.32 1088 95 Arg-Trp-D-Cys)-NH.sub.2 Ac-Oic-c(Asp-His-D-Phe-Arg- 1147.35 1147.4 97.5 Trp-Gaba-Lys)-NH.sub.2 Ac-Chg-c(Asp-His-D-Phe-Arg- 1135.33 1135.1 99 Trp-Gaba-Lys)-NH.sub.2 Ac-hCha-c(Asp-His-D-Phe-Arg- 1163.39 1163.4 99 Trp-Gaba-Lys)-NH.sub.2 Ac-D-Cha-c(Asp-His-D-Phe-Arg- 1149.36 1149.2 99 Trp-Gaba-Lys)-NH.sub.2 Ac-Nip-c(Asp-His-D-Phe-Arg- 1107.28 1107 98.9 Trp-Gaba-Lys)-NH.sub.2 Ac-hPro-c(Asp-His-D-Phe-Arg- 1107.28 1107.4 99 Trp-Gaba-Lys)-NH.sub.2 Ac-hLeu-c(Asp-His-D-Phe-Arg- 1123.32 1123.2 99 Trp-Gaba-Lys)-NH.sub.2 Ac-D-hCha-c(Asp-His-D-Phe- 1163.39 1163.6 94 Arg-Trp-Gaba-Lys)-NH.sub.2 Ac-Phe-c(Asp-His-D-Phe-Arg- 1143.31 1143.3 96.9 Trp-Gaba-Lys)-NH.sub.2 Ac-D-Phe-c(Asp-His-D-Phe-Arg- 1143.31 1143.3 96.5 Trp-Gaba-Lys)-NH.sub.2 Ac-D-Chg-c(Asp-His-D-Phe-Arg- 1135.33 1135.4 99 Trp-Gaba-Lys)-NH.sub.2 n-Butyryl-Cha-c(Asp-His-D-Phe- 1177.41 1177.5 88.6 Arg-Trp-Gaba-Lys)-NH.sub.2 Ac-hPhe-c(Asp-His-D-Phe-Arg- 1157.34 1157.2 70 Trp-Gaba-Lys)-NH.sub.2 Ac-β-hMet-c(Asp-His-D-Phe- 1141.36 1141.2 89 Arg-Trp-Gaba-Lys)-NH.sub.2 Ac-Gaba-c(Asp-His-D-Phe-Arg- 1081.24 1080.9 92.5 Trp-Gaba-Lys)-NH.sub.2 Ac-Cha-c(Asp-His-D-Phe-Arg-D- 1135.33 1135.2 85 Trp-Ala-Lys)-NH.sub.2 Ac-hCha-c(Asp-His-D-Phe-Arg- 1149.36 1149.1 87 D-Trp-Ala-Lys)-NH.sub.2 Ac-Leu-c(Asp-His-D-Phe-Arg-D- 1095.27 1095.4 98.6 Trp-Ala-Lys)-NH.sub.2 Ac-hLeu-c(Asp-His-D-Phe-Arg- 1109.3 1109.2 93.8 D-Trp-Ala-Lys)-NH.sub.2 Ac-Phe-c(Asp-His-D-Phe-Arg-D- 1129.29 1129.2 81.9 Trp-Ala-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1095.27 1095.3 97 Trp-D-Ala-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1095.27 1095.3 82 Trp-β-Ala-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1109.3 1109.1 99 Trp-Gaba-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1137.35 1137.4 98 Trp-Aha-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1123.32 1123.3 97.3 Trp-Apn-Lys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1102.35 1102 99 Trp-Apn-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1088.32 1087.8 97 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1116.38 1116.2 99 Trp-Ahx-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1074.3 1073.8 99.9 Trp-β-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1074.3 1073.8 99.9 Trp-D-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-2- 1124.36 1123.6 96.1 Nal-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-2- 1135.38 1134.5 99.1 Nal-Arg-2-Nal-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-2- 1135.38 1134.6 94.8 Nal-Arg-1-Nal-Cys)-NH.sub.2 nButanoyl-Nle-c(Cys-D-Ala-His- 1113.37 1112.6 95.7 D-Phe-Arg-2-Nal-Cys)-NH.sub.2 nButanoyl-Nle-c(Cys-D-Ala-His- 1102.35 1101.5 99.9 D-Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1085.32 1084.4 97.7 Arg-2-Nal-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1085.32 1084.5 96.6 Arg-1-Nal-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1091.35 1090.4 96.2 Arg-Bal-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Glu-His-D-Phe- 1132.33 1131.5 99.9 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg- 1095.27 1094.6 99.9 Trp-D-Ala-Lys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-2- 1141.41 1140.5 95.6 Nal-Arg-Bal-Cys)-NH.sub.2 Ac-Nle-c(Pen-D-Ala-His-D-Phe- 1102.35 1101.6 99.9 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1102.35 1101.6 99.9 Arg-Trp-Pen)-NH.sub.2 Ac-Nle-c(Pen-D-Ala-His-D-Phe- 1130.4 1129.6 99.9 Arg-Trp-Pen)-NH.sub.2 D-Phe-c(Cys-His-D-Phe-hArg- 1181.41 1181.7 96.9 Trp-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-(Et)Tyr-Arg- 1211.43 1211.7 97.1 Trp-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-Phe-Arg-Bip- 1204.44 1204.6 99 β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-(Et)Tyr-hArg- 1225.46 1225.7 97 Trp-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-Phe-hArg- 1218.47 1218.8 99 Bip-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-(Et)Tyr-hArg- 1262.52 1263 99 Bip-β-Ala-D-Cys)-Thr-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1131.35 1131.2 96.8 Arg-Trp-Gly-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1145.37 1145.3 96.4 Arg-Trp-D-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1145.37 1145.2 98.2 Arg-Trp-β-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1159.4 1159.2 95.1 Arg-Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1173.43 1173.3 96.8 Arg-Trp-Apn-Cys)-NH.sub.2 Nle-c(Cys-His-D-Phe-Arg-Trp- 1060.31 1060.3 98.5 Apn-Cys)-NH.sub.2 Ac-Nle-c(Asp-D-Ala-His-D-Phe- 1095.27 1094.7 96.2 Arg-Trp-Lys)-NH.sub.2 Ac-Nle-c(Asp-D-Ala-His-D-Phe- 1112.32 1111.7 96.5 Arg-Bal-Lys)-NH.sub.2 Ac-c(Cys-Glu-His-D-Phe-Arg- 1090.25 1089.6 99.9 Trp-Ala-Cys)-NH.sub.2 Ac-c(Cys-Glu-His-D-Phe-Arg-2- 1101.27 1100.6 98.3 Nal-Ala-Cys)-NH.sub.2 Ac-c(Cys-D-Ala-His-D-Phe-Arg- 1032.22 1031.5 95.2 Trp-Ala-Cys)-NH.sub.2 Ac-c(Cys-D-Ala-His-D-Phe-Arg- 1043.24 1042.5 95.6 2-Nal-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1144.39 1144.6 95.3 Arg-Trp-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1145.37 1144.6 97.3 Arg-Trp-β-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1158.41 1158.6 96.5 Arg-Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1103.33 1103 99.9 Arg-Trp-Pen)-OH Ac-Nle-c(Cys-D-Abu-His-D-Phe- 1088.32 1087.6 99.9 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Val-His-D-Phe- 1102.35 1101.7 99.9 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ile-His-D-Phe- 1116.38 1115.7 99.9 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Leu-His-D-Phe- 1116.38 1115.8 97.4 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Tle-His-D-Phe- 1116.38 1115.5 96.5 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Cha-His-D-Phe- 1156.44 1155.6 96.4 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Pen-His-D-Phe-Arg- 1116.38 1115.7 95 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg- 1116.38 1115.5 99.9 Trp-Gaba-Pen)-NH.sub.2 Ac-Nle-c(Pen-His-D-Phe-Arg- 1144.43 1144 99.9 Trp-Gaba-Pen)-NH.sub.2 Ac-Leu-c(Cys-His-D-Phe-Arg- 1088.32 1088 96.7 Trp-Gaba-Cys)-NH.sub.2 Ac-Cha-c(Cys-His-D-Phe-Arg- 1128.39 1128.4 95.8 Trp-Gaba-Cys)-NH.sub.2 Ac-Ile-c(Cys-His-D-Phe-Arg-Trp- 1088.32 1088.4 95 Gaba-Cys)-NH.sub.2 Ac-Phe-c(Cys-His-D-Phe-Arg- 1122.34 1122 95.2 Trp-Gaba-Cys)-NH.sub.2 Ac-Val-c(Cys-His-D-Phe-Arg- 1074.3 1074.6 95.4 Trp-Gaba-Cys)-NH.sub.2 Ac-2-Nal-c(Cys-His-D-Phe-Arg- 1172.4 1172.2 95.2 Trp-Gaba-Cys)-NH.sub.2 Nle-c(Cys-His-D-Phe-Arg-Trp- 1046.29 1046.4 97.6 Gaba-Cys)-NH.sub.2 Phe-c(Cys-His-D-Phe-Arg-Trp- 1080.3 1080 95.8 Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-3-Pal-D-Phe-Arg- 1099.35 1099.6 96.6 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1075.28 1075.2 99.9 Arg-Trp-Cys)-OH Ac-Nle-c(Cys-His-Phe-Arg-D- 1088.32 1088 95.8 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Asp-D-Ala-His-D-Phe- 1183.4 1182.85 99.9 Arg-Bal-Ala-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-2-Nal-Arg- 1145.33 1145 99.99 Trp-Ala-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-2-Nal-Arg- 1145.33 1145 99.99 Trp-βAla-Lys)-NH.sub.2 Ac-Nle-c(Cys-His-D-2-Nal-Arg- 1138.38 1137.8 99.99 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-2-Nal-Arg- 1166.44 1166 99 Trp-Ahx-Cys)-NH.sub.2 Ac-hPhe-c(Asp-His-D-2-Nal-Arg- 1207.4 1206.9 99 Trp-Gaba-Lys)-NH.sub.2 Ac-Cha-c(Asp-His-D-2-Nal-Arg- 1199.42 1198.8 100 Trp-Gaba-Lys)-NH.sub.2 Ac-Arg-c(Cys-D-Ala-His-D-Phe- 1117.3 1116.9 95.10 Arg-Trp-Cys)-NH.sub.2 Ac-D-Arg-c(Cys-D-Ala-His-D- 1117.33 1116.8 99.2 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-D-Arg-c(Cys-D-Ala-His-D- 1145.38 1144.9 96.4 Phe-Arg-Trp-Pen)-NH.sub.2 Ac-D-Arg-c(Cys-His-D-Phe-Arg- 1159.41 1158.9 99.9 Trp-Gaba-Pen)-NH.sub.2 Ac-Arg-c(Cys-His-D-Phe-Arg- 1159.41 1159.1 99 Trp-Gaba-Pen)-NH.sub.2 Ac-Arg-c(Cys-D-Ala-His-D-Phe- 1145.38 1145.1 99 Arg-Trp-Pen)-NH.sub.2 Ac-D-Arg-c(Asp-His-D-Phe-Arg- 1138.3 1138.0 98.0 Trp-Ala-Lys)-NH.sub.2 Ac-Arg-c(Asp-His-D-Phe-Arg- 1138.3 1138.1 99.0 Trp-Ala-Lys)-NH.sub.2
TABLE-US-00003 TABLE 1B Calculated Experimental Molecular Molecular Compound Weight Weight Purity Ac-Arg-c(Cys-D-Ala-His-D-2- 1167.39 1167.40 99.9 Nal-Arg-Trp-Cys)-NH.sub.2
Example 3: In Vitro Studies
[0643] Compounds of the present invention can be and were tested for activity as ligands of one or more of the melanocortin receptors according to the following procedures. One skilled in the art would know that procedures similar to those described herein may be used to assay the binding activities of the compounds of the invention to melanocortin receptor molecules.
Radioligand Binding Assays
[0644] Cellular membranes used for the in vitro receptor binding assays were obtained from transgenic CHO-K1 cells stably expressing hMC-R receptor subtypes 1, 3, 4 or 5. The CHO-K1 cells expressing the desired hMC-R receptor type were sonicated (Branson® setting 7, approximately 30 sec) in ice-cold 50 mM Tris-HCl at pH 7.4 and then centrifuged at 39,000 g for 10 minutes at approximately 4° C. The pellets were resuspended in the same buffer and centrifuged at 50,000 g for 10 minutes at approximately 4° C. The washed pellets containing the cellular membranes were stored at approximately −80° C.
[0645] Competitive inhibition of [.sup.125I](Tyr.sup.2)-(Nle.sup.4-D-Phe.sup.7)α-MSH ([.sup.125I]-NDP-α-MSH, Amersham Biosciences®) binding was carried out in polypropylene 96 well plates. Cell membranes (1-10 μg protein/well) prepared as described above were incubated in 50 mM Tris-HCl at pH 7.4 containing 0.2% bovine serum albumin (BSA), 5 mM MgCl.sub.2, 1 mM CaCl.sub.2 and 0.1 mg/mL bacitracin, with increasing concentrations of the test compound and 0.1-0.3 nM [.sup.125I]-NDP-α-MSH for approximately 90-120 minutes at approximately 37° C. Bound [.sup.125I]-NDP-α-MSH ligand was separated from free [.sup.125I]-NDP-α-MSH by filtration through GF/C glass fiber filter plates (Unifilter®; Packard) presoaked with 0.1% (w/v) polyethylenimine (PEI), using a Packard Filtermate® harvester. Filters were washed three times with 50 mM Tris-HCl at pH 7.4 at a temperature of approximately 0-4° C. and then assayed for radioactivity using a Packard Topcount® scintillation counter. Binding data were analyzed by computer-assisted non-linear regression analysis (XL fit; IDBS).
[0646] A selection of the preferred embodiments was tested using the above-discussed assay and the binding constants (Ki in nM) are reported in Tables 2A, 2B and 2C.
TABLES 2A, 2B and 2C—Radioligand Binding Assay Data for Selected Compounds
[0647]
TABLE-US-00004 TABLE 2A Ki Ki Ki Ki Ki hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-R MC4-R Ac-Arg-c(Cys-D-Ala-His-D- 3.87 10.1 2.09 430 1.9 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-D-Arg-c(Cys-D-Ala-His-D- 4.01 12.1 1.76 352 2.3 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-D-Arg-c(Cys-D-Ala-His-D- 8.29 13.3 2.78 816 3.0 Phe-Arg-Trp-Pen)-NH.sub.2 Ac-D-Arg-c(Cys-His-D-Phe- 3.93 172 11.0 538 0.36 Arg-Trp-Gaba-Pen)-NH.sub.2 Ac-Arg-c(Cys-His-D-Phe-Arg- 1.81 20.5 4.57 502 0.4 Trp-Gaba-Pen)-NH.sub.2 Ac-Arg-c(Cys-D-Ala-His-D- 9.67 22.0 4.2 1900 2.3 Phe-Arg-Trp-Pen)-NH.sub.2 Ac-D-Arg-c(Asp-His-D-Phe- 0.79 45.5 1.21 493 0.6 Arg-Trp-Ala-Lys)-NH.sub.2 Ac-Arg-c(Asp-His-D-Phe-Arg- 0.68 20.7 1.01 783 0.7 Trp-Ala-Lys)-NH.sub.2
TABLE-US-00005 TABLE 2B Ki Ki Ki Ki Ki hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-R MC4-R Ac-Nle-c(Cys-D-Ala-His-D-2- 114 63.9 3.07 1657 37.1 Nal-Arg-1-Nal-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 11 26 7.6 1800 1.4 Phe-Arg-Trp-Cys)-NH.sub.2 D-Phe-c(Cys-His-D-(Et)Tyr- 0.05 9.3 1.1 2.9 0.0 Arg-Trp-β-Ala-D-Cys)-Thr-NH.sub.2 Nle-c(Cys-His-D-Phe-Arg-Trp- 0.07 4.1 0.85 8.8 0.1 Apn-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg- 0.12 10 0.43 0.42 0.3 Trp-Gaba-Pen)-NH.sub.2 Nle-c(Cys-His-D-Phe-Arg-Trp- 0.05 1.3 0.47 0.2 0.1 Gaba-Cys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg- 0.0996 9318 0.617 10.9 0.16 Trp-β-Ala-Lys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg- .0132 16.1 1.23 0.359 0.11 Trp-Ahx-Cys)-NH.sub.2 D-Phe-c(Cys-His-D-Phe-Arg- 0.207 43.2 2.58 344 0.08 Trp-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-Phe-Arg- 0.420 106 4.75 1260 0.09 Trp-Gaba-D-Cys)-Thr-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg- 0.0951 9.33 0.894 13.4 0.11 Trp-Apn-Cys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg- 0.999 300 11.1 431 0.09 Trp-Apn-Lys)-NH.sub.2 Ac-Cha-c(Asp-His-D-Phe-Arg- 0.106 11.8 1.49 110 0.07 Trp-Gaba-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-Phe-Arg- 0.0506 9.89 1.04 16.3 0.05 Trp-Gaba-Lys)-NH.sub.2 Ac-Chg-c(Asp-His-D-Phe-Arg- 0.884 223 22.5 609 0.04 Trp-Gaba-Lys)-NH.sub.2 Ac-hCha-c(Asp-His-D-P-he- 0.721 93.5 56.0 747 0.01 Arg-Trp-Gaba-Lys)-NH.sub.2 Ac-D-Chg-c(Asp-His-D-Phe- 0.227 14.5 2.99 164 0.08 Arg-Trp-Gaba-Lys)-NH.sub.2 Ac-hPhe-c(Asp-His-D-Phe-Arg- 0.277 25.2 3.37 203 0.08 Trp-Gaba-Lys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe-Arg- 0.323 14.1 1.96 24.0 0.16 D-Trp-β-Ala-Cys)-NH.sub.2 Ac-Nle-c(Pen-D-Ala-His-D- 34.1 118 17.0 5560 2.01 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 29.1 22.8 3.84 2550 7.58 Phe-Arg-Trp-Pen)-NH.sub.2 D-Phe-c(Cys-His-D-Phe-hArg- 0.442 123 10.3 521 0.04 Trp-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-Phe-Arg- 5.80 3370 583 1130 0.01 Bip-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-(Et)Tyr- 0.0567 31.4 14.7 9.27 0 hArg-Trp-β-Ala-D-Cys)-Thr- NH.sub.2 D-Phe-c(Cys-His-D-Phe-hArg- 1.68 1260 172 1220 0.01 Bip-β-Ala-D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D-(Et)Tyr- 0.128 85.6 36.9 38.0 0 hArg-Bip-β-Ala-D-Cys)-Thr- NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 0.352 149 3.01 339 0.12 Phe-Arg-Trp-Gly-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 3.93 876 48.0 4940 0.08 Phe-Arg-Trp-D-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 0.995 287 4.80 766 0.21 Phe-Arg-Trp-β-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 0.848 184 3.76 956 0.23 Phe-Arg-Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 1.10 228 7.58 859 0.15 Phe-Arg-Trp-Apn-Cys)-NH.sub.2 Ac-Nle-c(Asp-D-Ala-His-D- 0.659 98.9 2.55 4.19 0.26 Phe-Arg-Trp-Lys)-NH.sub.2 Ac-Nle-c(Asp-D-Ala-His-D- 4.12 445 50.6 4300 0.08 Phe-Arg-Bal-Lys)-NH.sub.2 Ac-c(Cys-Glu-His-D-Phe-Arg- 111 1710 47.7 694 2.33 Trp-Ala-Cys)-NH.sub.2 Ac-c(Cys-Glu-His-D-Phe-Arg- 262 2500 96.4 1460 2.72 2-Nal-Ala-Cys)-NH.sub.2 Ac-c(Cys-D-Ala-His-D-Phe- 199 5990 96.7 >10000 2.06 Arg-Trp-Ala-Cys)-NH.sub.2 Ac-c(Cys-D-Ala-His-D-Phe- 132 4560 40.7 8810 3.24 Arg-2-Nal-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 9.12 1130 22.1 2860 0.41 Phe-Arg-Trp-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 1.00 227 5.55 496 0.18 Phe-Arg-Trp-β-Ala-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 0.536 169 3.12 358 0.17 Phe-Arg-Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 32.1 330 17.4 165 1.84 Phe-Arg-Trp-Pen)-OH Ac-Nle-c(Cys-D-Abu-His-D- 10.6 41.1 7.69 54.9 1.38 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Val-His-D- 13.0 104 10.1 40 1.29 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ile-His-D-Phe- 4.28 38.5 9.0 12.5 0.48 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Leu-His-D- 1.60 6.82 4.13 5.57 0.39 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Tle-His-D-Phe- 12.0 85.8 11.2 40 1.07 Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Cha-His-D- 0.353 2.08 1.41 0.857 0.25 Phe-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Pen-His-D-Phe-Arg- 0.537 86.1 5.89 2.56 0.09 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Pen-His-D-Phe-Arg- 0.744 178 3.51 2.69 0.21 Trp-Gaba-Pen)-NH.sub.2 Ac-Leu-c(Cys-His-D-Phe-Arg- 0.216 17.4 0.995 0.486 0.22 Trp-Gaba-Cys)-NH.sub.2 Ac-Cha-c(Cys-His-D-Phe-Arg- 0.107 9.11 0.884 0.354 0.12 Trp-Gaba-Cys)-NH.sub.2 Ac-Ile-c(Cys-His-D-Phe-Arg- 0.148 13.9 1.06 0.423 0.14 Trp-Gaba-Cys)-NH.sub.2 Ac-Phe-c(Cys-His-D-Phe-Arg- 0.254 18.5 2.13 0.714 0.12 Trp-Gaba-Cys)-NH.sub.2 Ac-Val-c(Cys-His-D-Phe-Arg- 0.256 29.9 1.98 0.864 0.13 Trp-Gaba-Cys)-NH.sub.2 Ac-2-Nal-c(Cys-His-D-Phe- 0.560 39.2 2.94 2.73 0.19 Arg-Trp-Gaba-Cys)-NH.sub.2 Phe-c(Cys-His-D-Phe-Arg-Trp- 0.186 15.2 4.93 0.537 0.04 Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-3-Pal-D-Phe-Arg- 21.1 151 10.4 92.6 2.03 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D- 30.7 152 15.6 114 1.97 Phe-Arg-Trp-Cys)-OH Ac-Nle-c(Cys-His-Phe-Arg-D- 5.20 150 138 20.3 0.04 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Asp-D-Ala-His-D- 4.89 290 21.3 11.1 0.23 Phe-Arg-Bal-Ala-Lys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-2- 25.5 3.82 7.61 102 3.35 Nal-Arg-Trp-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-2- 32.5 5.85 2.53 94.6 12.85 Nal-Arg-2-Nal-Cys)-NH.sub.2 Ac-Nle-c(Cys-D-Ala-His-D-2- 22.2 12.7 16.6 125 1.34 Nal-Arg-Bal-Cys)-NH.sub.2 Ac-Nle-c(Asp-His-D-2-Nal- 1.17 1.56 0.277 3.24 4.22 Arg-Trp-Ala-Lys)-NH.sub.2 Ac-Nle-c(Asp-His-D-2-Nal- 0.648 2.78 0.329 1.4 1.97 Arg-Trp-β-Ala-Lys)-NH.sub.2 Ac-Nle-c(Cys-His-D-2-Nal-Arg- 0.393 1.86 0.375 1.11 1.05 Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-2-Nal-Arg- 0.333 2.91 0.998 0.366 0.33 Trp-Ahx-Cys)-NH.sub.2 Ac-hPhe-c(Asp-His-D-2-Nal- 0.461 2.45 0.931 1.37 0.50 Arg-Trp-Gaba-Lys)-NH.sub.2 Ac-Cha-c(Asp-His-D-2-Nal- 0.576 3.98 2.82 3.91 0.20 Arg-Trp-Gaba-Lys)-NH.sub.2
TABLE-US-00006 TABLE 2C Ki Ki Ki Ki Ki hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-R MC4-R Ac-Arg-c(Cys-D-Ala-His-D-2- 17.9 1.68 0.256 23.4 69.9 Nal-Arg-Trp-Cys)-NH.sub.2
Cyclic AMP Bioassay
[0648] Intracellular cyclic AMP (cAMP) levels were determined by an electrochemiluminescence (ECL) assay (Meso Scale Discovery®, Gaithersburg, Md.; referred to hereinafter as MSD). CHO-K1 cells stably expressing the hMC receptor subtypes were suspended in RMPI 1640® assay buffer (RMPI 1640 buffer contains 0.5 mM isobutylmethylxanthine (IBMX), and 0.2% protein cocktail (MSD blocker A)). Transgenic CHO-K1 cells stably expressing hMC receptor subtypes 1, 3, 4 or 5 were dispensed at a density of approximately 7,000 cells/well in 384-well Multi-Array® plates (MSD) containing integrated carbon electrodes and coated with anti-cAMP antibody. Increasing concentrations of the test compounds were added and the cells were incubated for approximately 40 minutes at approximately 37° C. Following this incubation, lysis buffer (HEPES-buffered saline solution with MgCl.sub.2 and Triton X-100® at ph 7.3) containing 0.2% protein cocktail and 2.5 nM TAG™ ruthenium-labeled cAMP (MSD) was added and the cells were incubated for approximately 90 minutes at room temperature. At the end of the second incubation period read buffer (Tris-buffered solution containing an ECL co-reactant and Triton X-100 at ph 7.8) was added and the cAMP levels in the cell lysates were immediately determined by ECL detection with a Sector Imager 6000 Reader® (MSD). Data were analyzed using a computer-assisted non-linear regression analysis (XL fit; IDBS) and reported as either an EC.sub.50 value or a Kb value.
[0649] EC.sub.50 represents the concentration of an agonist compound needed to obtain 50% of the maximum reaction response, e.g., 50% of the maximum level of cAMP as determined using the assay described above. The Kb value reflects the potency of an antagonist and is determined by Schild analysis. In brief, concentration-response curves of an agonist are carried out in the presence of increasing concentrations of an antagonist. The Kb value is the concentration of antagonist which would produce a 2-fold shift in the concentration-response curve for an agonist. It is calculated by extrapolating the line on a Schild plot to zero on the y-axis.
[0650] A selection of compounds was tested using the above-discussed assays and the results are reported in Tables 3A, 3B, 3C, and 3D.
TABLES 3A, 3B, 3C, and 3D—cAMP Bioassay Data for Selected Compounds
TABLE-US-00007 TABLE 3A EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-R MC4-R Ac-Arg-c(Cys-D-Ala-His- 5.79 5.25 0.313 1630 18.0 D-Phe-Arg-Trp-Cys)- NH.sub.2 Ac-D-Arg-c(Cys-D-Ala- 6.17 5.6 0.397 1020 16.0 His-D-Phe-Arg-Trp-Cys)- NH.sub.2 Ac-D-Arg-c(Cys-D-Ala- 26.5 10.5 0.493 2440 54.0 His-D-Phe-Arg-Trp-Pen)- NH.sub.2 Ac-D-Arg-c(Cys-His-D- 8.43 32.4 0.959 2140 9.0 Phe-Arg-Trp-Gaba-Pen)- NH.sub.2 Ac-Arg-c(Cys-His-D- 4.23 8.09 0.719 23.2 6.0 Phe-Arg-Trp-Gaba-Pen)- NH.sub.2 Ac-Arg-c(Cys-D-Ala-His- 48.3 13.3 0.79 10000 61.0 D-Phe-Arg-Trp-Pen)- NH.sub.2 Ac-D-Arg-c(Asp-His-D- 1.48 5.76 0.078 297 19.0 Phe-Arg-Trp-Ala-Lys)- NH.sub.2 Ac-Arg-c(Asp-His-D- 1.39 2.89 0.055 467 25.0 Phe-Arg-Trp-Ala-Lys)- NH.sub.2 ND = not determined
TABLE-US-00008 TABLE 3B EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-R MC4-R Ac-Nle-c(Cys-D-Ala-His- 2.4 0.33 0.078 420 31 D-Phe-Arg-Trp-Cys)- NH.sub.2 D-Phe-c(Cys-His-D- 0.35 1.1 0.11 0.37 3 (Et)Tyr-Arg-Trp-β-Ala- D-Cys)-Thr-NH.sub.2 Nle-c(Cys-His-D-Phe- 0.31 0.27 0.018 3.1 17 Arg-Trp-Apn-Cys)-NH.sub.2 Ac-Nle-c(Cys-His-D-Phe- 0.28 0.24 0.028 3.9 10 Arg-Trp-Gaba-Pen)-NH.sub.2 Nle-c(Cys-His-D-Phe- 0.37 0.1 0.021 1.7 18 Arg-Trp-Gaba-Cys)-NH.sub.2 Ac-Nle-c(Asp-His-D- 0.834 0.145 0.128 2.79 6.52 Phe-Arg-Trp-β-Ala-Lys)- NH.sub.2 Ac-Nle-c(Cys-His-D-Phe- 0.76 0.199 0.0492 1.73 15.45 Arg-Trp-Apn-Cys)-NH.sub.2 Ac-Cha-c(Asp-His-D- 3.26 0.189 0.0949 30.2 34.35 Phe-Arg-Trp-Gaba-Lys)- NH.sub.2 Ac-Nle-c(Asp-His-D- 1.37 0.628 0.131 3.48 10.46 Phe-Arg-Trp-Gaba-Lys)- NH.sub.2 Ac-hCha-c(Asp-His-D- 2.27 3.32 7.24 415 0.31 Phe-Arg-Trp-Gaba-Lys)- NH.sub.2 Ac-Nle-c(Pen-D-Ala-His- ND 1.89 0.531 ND ND D-Phe-Arg-Trp-Cys)- NH.sub.2 Ac-Nle-c(Cys-D-Ala-His- 14.3 2.03 0.183 2240 78.14 D-Phe-Arg-Trp-Pen)- NH.sub.2 D-Phe-c(Cys-His-D- 0.345 2.71 5376 2.38 0.06 (Et)Tyr-hArg-Trp-β-Ala- D-Cys)-Thr-NH.sub.2 D-Phe-c(Cys-His-D- 0.685 81.8 86.9 31.8 0.01 (Et)Tyr-hArg-Bip-β-Ala- D-Cys)-Thr-NH.sub.2 Ac-Nle-c(Asp-D-Ala-His- 0.931 3.22 1.65 >10000 0.56 D-Phe-Arg-Bal-Lys)-NH.sub.2 Ac-Nle-c(Cys-D-Leu-His- 3.24 0.465 0.0915 78.5 35.41 D-Phe-Arg-Trp-Cys)- NH.sub.2 Ac-Nle-c(Cys-D-Cha- 0.819 0.541 0.453 45.3 1.81 His-D-Phe-Arg-Trp-Cys)- NH.sub.2 ND = not determined
TABLE-US-00009 TABLE 3C EC50 Kb Kb EC50 Compound hMC1-R hMC3-R MC4-R hMC5-R Ac-Nle-c(Cys-D-Ala-His- 17.6 12.4 38.8 11.8 D-2-Nal-Arg-Trp-Cys)- NH.sub.2 Ac-Nle-c(Asp-His-D-2- 0.619 2.98 0.109 0.189 Nal-Arg-Trp-Ala-Lys)- NH.sub.2 Ac-Nle-c(Asp-His-D-2- 0.913 0.536 0.346 0.489 Nal-Arg-Trp-β-Ala-Lys)- NH.sub.2 Ac-Nle-c(Cys-His-D-2- 0.231 18.4 0.782 0.153 Nal-Arg-Trp-Gaba-Cys)- NH.sub.2 Ac-Nle-c(Cys-His-D-2- 0.581 10.8 0.967 0.126 Nal-Arg-Trp-Ahx-Cys)- NH.sub.2 Ac-hPhe-c(Asp-His-D-2- 0.413 9.32 0.824 0.307 Nal-Arg-Trp-Gaba-Lys)- NH.sub.2 Ac-Cha-c(Asp-His-D-2- 1.27 3.02 0.442 0.736 Nal-Arg-Trp-Gaba-Lys)- NH.sub.2 Ac-Nle-c(Cys-D-Ala-His- 383 61.5 53.6 2842 D-2-Nal-Arg-l-Nal-Cys)- NH.sub.2
TABLE-US-00010 TABLE 3D EC50 Kb Kb EC50 Compound hMC1-R hMC3-R MC4-R hMC5-R Ac-Arg-c(Cys-D-Ala-His- 193 5.72 1.58 1111 D-2-Nal-Arg-Trp-Cys)- NH.sub.2
Example 4: In Vivo Studies
[0651] Compounds of the present invention can be and were tested for an effect upon food intake and/or body weight according to the following procedures. One skilled in the art would know that procedures similar to those described herein may be used to assay the effect of the compounds of the invention upon food intake and/or body weight.
[0652] Ligand compounds activating melanocortin receptors tested in the in vivo studies were as follows (Table 4):
TABLE-US-00011 TABLE 4 Ligand Code Structure Compound A Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2 Compound B Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2 Compound C Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH.sub.2 Compound D D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D- Cys)-Thr-NH.sub.2 Compound E Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2 Compound F Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH.sub.2 Compound G Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH.sub.2
Acute Feeding Experiments (Fasting)
[0653] Male Sprague Dawley rats (250 g) were housed in individual cages and maintained under 12:12 hour light:dark conditions. The rats were fasted for 18 hours prior to the start of the experiment with water available ad libitum. At time 0, the rats were injected subcutaneously (sc) with selected compounds at doses of either 500 or 100 nmole/kg, or with vehicle, and were provided with food. Individual food consumption was measured at about 1, 2, 3, 4, 5 and 6 hours after injection. Data for selected compounds of the invention are reported in
Acute Feeding Experiments (Non Fasting)
[0654] Male Sprague Dawley rats (250 g) are housed in individual cages and maintained under 12:12 hour light:dark conditions. Food and water is available ad libitum throughout the experiment. At time 0, the rats are injected sc with compound at doses of either 500 or 100 nmole/kg, or with vehicle. Individual food consumption is measured at about 1, 2, 3, 4, 5 and 6 hours after injection.
Chronic Feeding Experiments
[0655] Male Sprague Dawley rats (250 g) were housed in individual cages and maintained under 12:12 hour light:dark conditions with both food and water available ad libitum. The rats were injected sc 3×/day (approximately 0800 hour, 1200 hour, and 1600 hour) with compound at various doses or with vehicle for 7 days. Individual body weight and food consumption were measured daily. Data for selected compounds of the invention are reported in
Administration and Use
[0656] The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of polylactic-glycolic acids). A typical method of making a salt of a peptide of the present invention is well known in the art and can be accomplished by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt results from the purification of the peptide by using preparative HPLC, eluting with TFA containing buffer solutions) can be converted into another salt, such as an acetate salt, by dissolving the peptide in a small amount of 0.25 N acetic acid aqueous solution. The resulting solution is applied to a semi-prep HPLC column (Zorbax®, 300 SB, C-8). The column is eluted with: (1) 0.1N ammonium acetate aqueous solution for 0.5 hours; (2) 0.25N acetic acid aqueous solution for 0.5 hours; and (3) a linear gradient (20% to 100% of solution B over 30 minutes) at a flow rate of 4 ml/min (solution A is 0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid in acetonitrile/water, 80:20). The fractions containing the peptide are collected and lyophilized to dryness.
[0657] As is well known to those skilled in the art, the known and potential uses of peptides with melanocortin receptor (MC-R) agonist or antagonist activity is varied and multitudinous, thus the administration of the compounds of this invention for purposes of eliciting an agonist effect can have the same effects and uses as melanocortin itself.
[0658] Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula (I) in association with a pharmaceutically acceptable carrier.
[0659] The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. In general, an effective dosage for the activities of this invention is in the range of 1×10.sup.−7 to 200 mg/kg/day, preferably 1×10.sup.−4 to 100 mg/kg/day which can be administered as a single dose or divided into multiple doses.
[0660] The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
[0661] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
[0662] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
[0663] Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Preparations may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. Preparations can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
[0664] Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
[0665] Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
[0666] Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications. U.S. Pat. No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form. U.S. Pat. No. 5,821,221 teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. Pat. No. 5,916,883 teaches sustained release compositions comprising a bioactive agent and cyclodextrin. The teachings of the foregoing patents and applications are incorporated herein by reference.