Peptides as oxytocin agonists

Abstract

The present compounds compounds are oxytocin receptor agonists for the treatment of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.

Claims

1. A compound of formula ##STR00059## wherein R.sup.1 is methyl or cyclopropyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen, lower alkyl, lower alkyl substituted by hydroxy, (CH.sub.2).sub.2C(O)NH.sub.2, benzyl, phenyl, CH.sub.2-five membered aromatic heterocyclic group, CH.sub.2-indolyl, CH.sub.2-cycloalkyl, cycloalkyl or (CH.sub.2).sub.2S-lower alkyl; R.sup.3 is hydrogen or lower alkyl; or X is C(O)CHR.sup.4CHR.sup.4C(O)NHCH.sub.2 R.sup.4/R.sup.4 are hydrogen or one of R.sup.4 or R.sup.4 is amino: o is 0 or 1; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

2. A compound of formula I according to claim 1, wherein o is 0.

3. A compound of formula I according to claim 1, selected from the group consisting of ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##

4. A pharmaceutical composition comprising a compound of formula I according to claim 1, and a pharmaceutical acceptable carrier and/or adjuvant.

5. A method of inhibiting the oxytocin receptor in a cell, comprising administering to the cell a compound of formula I according to claim 1.

6. A method of treating a disorder selected from autism, stress, an anxiety disorder, depression, schizophrenia, a psychiatric disorder, memory loss, alcohol withdrawal, drug addiction, or Prader-Willi Syndrome, comprising administering to a subject in need thereof a compound of formula I according to claim 1.

7. The method of claim 6, wherein the disorder is stress or an anxiety disorder.

8. The method of claim 7, wherein the disorder is post-traumatic stress disorder or anxiety.

Description

EXAMPLE 1

(1) ##STR00014##

(2) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 971.1; observed 971.2

EXAMPLE 2

(3) ##STR00015##

(4) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Sar-OH, Fmoc-Dap(Aloc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and Fmoc-Asp(Allyl)-OH. MS (M+H.sup.+): expected 960.0; observed 960.8

EXAMPLE 3

(5) ##STR00016##

(6) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 945.0; observed 945.5

EXAMPLE 4

(7) ##STR00017##

(8) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-SAR-OH, Fmoc-Dap(Aloc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-D-AspOAllyl. MS (M+H.sup.+): expected 960.0; observed 960.8

EXAMPLE 5

(9) ##STR00018##

(10) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 931.0; observed 931.1

EXAMPLE 6

(11) ##STR00019##

(12) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nva-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 945.0; observed 945.2

EXAMPLE 7

(13) ##STR00020##

(14) The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeVal-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 985.0; observed 985.2

EXAMPLE 8

(15) ##STR00021##

(16) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Met-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 989.1; observed 989.5

EXAMPLE 9

(17) ##STR00022##

(18) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 971.0; observed 971.5

EXAMPLE 10

(19) ##STR00023##

(20) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 959.0; observed 959.5

EXAMPLE 11

(21) ##STR00024##

(22) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 945.0; observed 945.5

EXAMPLE 12

(23) ##STR00025##

(24) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 957.0; observed 957.6

EXAMPLE 13

(25) ##STR00026##

(26) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Gln(Trt)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 986.0; observed 986.5

EXAMPLE 14

(27) ##STR00027##

(28) The following amino acids were used: Fmoc-Gly-OH, Fmoc-PheOH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 1005.0; observed 1006.8

EXAMPLE 15

(29) ##STR00028##

(30) The following amino acids were used: Fmoc-Gly-OH, Fmoc-His(Trt)OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 995.0; observed 996.7

EXAMPLE 16

(31) ##STR00029##

(32) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Trp(Boc)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 1044.10; observed 1045.4

EXAMPLE 17

(33) ##STR00030##

(34) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nva-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 957.0; observed 957.5

EXAMPLE 18

(35) ##STR00031##

(36) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Cha-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 1011.1; observed 1011.5

EXAMPLE 19

(37) ##STR00032##

(38) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phg-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 991.0; observed 991.5

EXAMPLE 20

(39) ##STR00033##

(40) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 997.0; observed 997.5

EXAMPLE 21

(41) ##STR00034##

(42) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thi-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 1011.1; observed 1011.4

EXAMPLE 22

(43) ##STR00035##

(44) The following amino acids were used: Fmoc-Gly-OH, Fmoc-homoLeu-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 985.1; observed 985.5

EXAMPLE 23

(45) ##STR00036##

(46) The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeLeu-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 959.0; observed 959.5

EXAMPLE 24

(47) ##STR00037##

(48) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 971.0; observed 971.2

EXAMPLE 25

(49) ##STR00038##

(50) The following amino acids were used: Fmoc-Gly-OH, Fmoc-homoLeu-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 959.0; observed 959.1

EXAMPLE 26

(51) ##STR00039##

(52) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Met-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 963.1; observed 963.6

EXAMPLE 27

(53) ##STR00040##

(54) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nva-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 931.0; observed 931.5

EXAMPLE 28

(55) ##STR00041##

(56) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 945.0; observed 945.5

EXAMPLE 29

(57) ##STR00042##

(58) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 933.0; observed 933.6

EXAMPLE 30

(59) ##STR00043##

(60) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 919.0; observed 919.4

EXAMPLE 31

(61) ##STR00044##

(62) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Cha-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 985.1; observed 985.6

EXAMPLE 32

(63) ##STR00045##

(64) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Gln(Trt)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 960.0; observed 960.8

EXAMPLE 33

(65) ##STR00046##

(66) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phe-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 979.0; observed 979.3

EXAMPLE 34

(67) ##STR00047##

(68) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thi-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 985.1; observed 985.6

EXAMPLE 35

(69) ##STR00048##

(70) The following amino acids were used: Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 969.0; observed 969.9

EXAMPLE 36

(71) ##STR00049##

(72) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Trp(Boc)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 1018.0; observed 1018.6

EXAMPLE 37

(73) ##STR00050##

(74) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phg-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H.sup.+): expected 965.0; observed 965.2

EXAMPLE 38

(75) ##STR00051##

(76) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(77) MS (M+H.sup.+): expected 971.1; observed 971.8

EXAMPLE 39

(78) ##STR00052##

(79) The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeVal-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(80) MS (M+H.sup.+): expected 985.1; observed 985.6

EXAMPLE 40

(81) ##STR00053##

(82) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(83) MS (M+H.sup.+): expected 957.0; observed 957.5

EXAMPLE 41

(84) ##STR00054##

(85) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Aib-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(86) MS (M+H.sup.+): expected 943.0; observed 943.5

EXAMPLE 42

(87) ##STR00055##

(88) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(89) MS (M+H.sup.+): expected 971.1; observed 971.6

EXAMPLE 43

(90) ##STR00056##

(91) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(92) MS (M+H.sup.+): expected 997.1; observed 997.6

EXAMPLE 44

(93) ##STR00057##

(94) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(95) MS (M+H.sup.+): expected 959.0; observed 959.5

EXAMPLE 45

(96) ##STR00058##

(97) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.

(98) MS (M+H.sup.+): expected 945.0; observed 945.5

(99) Material and Methods

(100) Cell Culture and Stable Clone Production

(101) Chines Hamster Ovary (CHO) cells were transfected with expression plasmids encoding either the human V1a, the human Oxytocin (OTR) or the human V2 receptor, the later in combination with the chimeric Gqs5 G protein to redirect the signal to Calcium flux. Stable cells were cloned by limiting dilution to yield monoclonal cell lines expressing either human V1a, human V2+Gqs5 or human OTR receptors and selected based on functional responses detected on a fluorometric imaging plate reader (FLIPR) detecting Calcium flux in the cell after receptor activation. The stable cell lines were grown in F-12 K Nutrient Mixture (Kaighns Modification), containing 10% foetal bovine serum (FBS), 1% penicillin-streptomycin, 1% L-glutamate, 200 ug/ml Geneticin at 37 C. in a 10% CO.sub.2 incubator at 95% humidity.

(102) Calcium Flux Assays Using Fluorescent Imaging (Fluorometric Imaging Plate Reader, FLIPR)

(103) On the afternoon before the assay, cells were plated at a density of 50,000 cells/well into black 96 well plates with clear bottoms to allow cell inspection and fluorescence measurements from the bottom of each well. The density of cells was sufficient to yield a confluent monolayer the next day. Hanks balanced salt solution, without phenol red, containing 20 mM HEPES (pH 7.3) and 2.5 mM probenecid (assay buffer) was prepared fresh for each experiment. Compound dilutions were made using a Beckman Biomek 2000 laboratory automation workstation, in assay buffer containing 1% DMSO. The dye-loading buffer consisted of a final concentration of 2 M Fluo-4-AM (dissolved in DMSO and pluronic acid) in assay buffer. The existing culture media was removed from the wells and 100 l of the dye-loading buffer was added to each well and incubated for approximately 60 min at 37 C. in a 5% CO.sub.2 incubator at 95% humidity. Once dye-loaded, the cells were washed thoroughly on an Embla cell washer with the assay buffer to remove any unincorporated dye. Exactly 100 l assay buffer was left in each well.

(104) Each 96 well plate containing dye-loaded cells was placed into the FLIPR machine and the laser intensity set to a suitable level to detect low basal fluorescence. To test compounds as agonists, 25 l diluted compound was added to the plate 10 seconds into the fluorescent measurements and fluorescent response was recorded for 5 minutes. The fluorescence data was normalized to the endogenous full agonist dose-response set at 100% for the maximum response and 0% for the minimum. Each agonist concentration-response curve was constructed using a four parameter logistic equation with Microsoft Excel XLFit as follows: Y=Minimum+((MaximumMinimum)/(1+10.sup.(LogEC50-X)nH)), where y is the % normalized fluorescence, minimum is the minimum y, maximum is the maximum y, logEC.sub.50 is the log.sub.10 concentration which produces 50% of the maximum induced fluorescence, x is the log.sub.10 of the concentration of the agonist compound and H is the slope of the curve (the Hill Coefficient). The maximum value gives the efficacy of the agonist test compound in percentage. The concentration of agonist that produced a half-maximal response is represented by the EC.sub.50 value, the logarithm of which yielded the pEC.sub.50 value.

(105) The following EC.sub.50 (nM), and efficacy (%) for the specific peptides may be provided, together with comparative data for hV1a and hV2:

(106) TABLE-US-00001 hOT hV2 EC.sub.50(nM)/ hV1a EC.sub.50 (nM)/ Expl. efficacy (%) EC.sub.50 (nM) efficacy (%) 1 1/105 5125 216/130 2 4/144 >27000 3 0.9/113.sup. >27000 612/130 4 5/126 5 0.7/111.sup. >27000 1126/123 6 1/119 >27000 364/104 7 3/101 8 1/134 9 1/132 10 1/130 11 3/128 12 1.6/130.sup. 13 8/128 14 6/122 15 8/123 16 4/100 17 0.6/114.sup. 351 116/116 18 2/130 19 0.4/114.sup. 470 59/114 20 0.9/117.sup. 562 174/112 21 4/126 22 0.8/109.sup. 391 176/106 23 3/123 24 0.5/104.sup. >27000 152/120 25 0.8/103.sup. >27000 213/118 26 0.5/107.sup. >27000 281/119 27 0.8/107.sup. >27000 282/114 28 0.5/109.sup. >27000 1385/119 29 0.6/109.sup. >27000 2068/113 30 2/109 31 0.5/107.sup. >27000 199/126 32 5/112 33 3/111 34 3/106 35 4/111 36 2/111 37 0.2/112.sup. >27000 53/121 38 0.38/126 >27000 626/146 39 1.3/108.sup. 40 0.6/106.sup. 41 2.5/108.sup. 42 0.37/115 43 0.26/110 44 0.9/115.sup. 45 0.8/117.sup.

(107) The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered preferably transdermal, intranasal, subcutaneous or intra venous (iv).

(108) Transdermal is a route of administration wherein active ingredients are delivered across the skin for systematic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes.

(109) Nasal administration can be used to deliver drugs for either local or systemic effects, nasal sprays for local effect are quite common. Peptide drugs may be administered as nasal sprays to avoid drug degradation after oral administration.

(110) Subcutaneous injections are also common for the administration of peptide drugs. An intramuscular injection is the injection of a substance directly into the muscle. It is one of several alternative methods for the administration of medications. It is often used for particular forms of medication that are administered in small amounts. The injections should be given under the skin.

(111) The intravenous route is the infusion of liquid substances directly into a vein. Compared with other routes of administration, the intravenous route is the fastest way to deliver fluids and medications throughout the body.

(112) The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

(113) Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

(114) The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory, loss alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.

(115) The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. The dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.