Neuropeptide FF receptor modulators based on a proline scaffold are provided which offer NPFF receptor potencies in the nanomolar range and antagonistic selectivity for the NPFF1 receptor. Methods, compounds and compositions for modulating the function of neuropeptide FF receptors are provided for pharmacotherapies capable of influencing conditions or disorders affected by the neuropeptide FF receptors.

The present disclosure relates to the field of pharmaceutical chemistry, and particularly to a compound represented by Formula (I), a preparation method and medical use thereof. In the compound represented by Formula (I), a lactulosyl group is connected to a heteroatom of genin (G) via a glycosidic bond, wherein the genin (G) is a group formed by removing one hydrogen atom from a heteroatom of an active pharmaceutical molecule, and “” indicates that the lactulosyl group is connected to the heteroatom of the genin (G) via an α-glycosidic bond or a β-glycosidic bond. Pharmacokinetic experiments prove that the lactuloside compound according to the present disclosure can pass through the gastrointestinal tract of a mammal without being absorbed significantly by the gastrointestinal tract and hydrolyzed significantly by endogenous enzymes of a mammal host. Therefore, the lactuloside compound can arrive at the colon site of the mammal, and release an active drug in the colon under the action of colon flora. The lactuloside compound has a function of colon-localized drug release, and can be used for preventing or treating an intestinal disease. ##STR00001##

The present disclosure relates to the field of pharmaceutical chemistry, and particularly to a compound represented by Formula (I), a preparation method and medical use thereof. In the compound represented by Formula (I), a lactulosyl group is connected to a heteroatom of genin (G) via a glycosidic bond, wherein the genin (G) is a group formed by removing one hydrogen atom from a heteroatom of an active pharmaceutical molecule, and “” indicates that the lactulosyl group is connected to the heteroatom of the genin (G) via an α-glycosidic bond or a β-glycosidic bond. Pharmacokinetic experiments prove that the lactuloside compound according to the present disclosure can pass through the gastrointestinal tract of a mammal without being absorbed significantly by the gastrointestinal tract and hydrolyzed significantly by endogenous enzymes of a mammal host. Therefore, the lactuloside compound can arrive at the colon site of the mammal, and release an active drug in the colon under the action of colon flora. The lactuloside compound has a function of colon-localized drug release, and can be used for preventing or treating an intestinal disease. ##STR00001##

5-HT receptor agonists are useful in the treatment of a variety of diseases. Provided herein are methods of reducing the incidence and/or severity of seizures in a human patient using a 5-HT receptor agonist, such as, for example, a 5-HT4 agonist (e.g., fenfluramine). Methods of treating epilepsy or epileptic encephalopathy, and/or reducing, ameliorating or eliminating incidence of SUDEP in a subject diagnosed with epilepsy by administering a 5-HT4 agonist (e.g., fenfluramine) to a subject in need thereof are provided. Pharmaceutical compositions for use in practicing the subject methods are also provided.

5-HT receptor agonists are useful in the treatment of a variety of diseases. Provided herein are methods of reducing the incidence and/or severity of seizures in a human patient using a 5-HT receptor agonist, such as, for example, a 5-HT4 agonist (e.g., fenfluramine). Methods of treating epilepsy or epileptic encephalopathy, and/or reducing, ameliorating or eliminating incidence of SUDEP in a subject diagnosed with epilepsy by administering a 5-HT4 agonist (e.g., fenfluramine) to a subject in need thereof are provided. Pharmaceutical compositions for use in practicing the subject methods are also provided.

5-HT receptor agonists are useful in the treatment of a variety of diseases. Provided herein are methods of reducing the incidence and/or severity of seizures in a human patient using a 5-HT receptor agonist, such as, for example, a 5-HT4 agonist (e.g., fenfluramine). Methods of treating epilepsy or epileptic encephalopathy, and/or reducing, ameliorating or eliminating incidence of SUDEP in a subject diagnosed with epilepsy by administering a 5-HT4 agonist (e.g., fenfluramine) to a subject in need thereof are provided. Pharmaceutical compositions for use in practicing the subject methods are also provided.

The present invention provides a composition which comprises a compound which is a mixture of deuterium containing and non-deuterium containing molecules having the structure:

##STR00001## wherein R.sub.1 is

##STR00002## wherein at least one of H.sub.1, H.sub.2 or H.sub.3 is a deuterium-enriched —H site, or

##STR00003## wherein at least one of H.sub.1, H.sub.2, H.sub.3, H.sub.4 or H.sub.5 is a deuterium-enriched —H site,
or a pharmaceutically acceptable salt of the compound, and methods of using the composition to treat pain, depressive disorders, mood disorders, anxiety disorders, opioid use disorders, and opioid withdrawal symptoms.

The present invention provides a composition which comprises a compound which is a mixture of deuterium containing and non-deuterium containing molecules having the structure:

##STR00001## wherein R.sub.1 is

##STR00002## wherein at least one of H.sub.1, H.sub.2 or H.sub.3 is a deuterium-enriched —H site, or

##STR00003## wherein at least one of H.sub.1, H.sub.2, H.sub.3, H.sub.4 or H.sub.5 is a deuterium-enriched —H site,
or a pharmaceutically acceptable salt of the compound, and methods of using the composition to treat pain, depressive disorders, mood disorders, anxiety disorders, opioid use disorders, and opioid withdrawal symptoms.

The present invention provides a method of treating a respiratory illness in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound comprising a reaction product of a reaction mixture comprising: a) N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide or a derivative thereof; and b) dimethyl sulfoxide. Also provided are methods of alleviating opioid addiction while suppressing withdrawal symptoms and alleviating inflammation and visceral pain with minimal risk of addiction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound described above.

The present invention provides a method of treating a respiratory illness in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound comprising a reaction product of a reaction mixture comprising: a) N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide or a derivative thereof; and b) dimethyl sulfoxide. Also provided are methods of alleviating opioid addiction while suppressing withdrawal symptoms and alleviating inflammation and visceral pain with minimal risk of addiction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound described above.