t-226296 and Disease-Models--Animal

We report here new chemical series acting as antagonists of melanin-concentrating hormone receptor 1 (MCHR-1). Synthesis and structure-activity relationships are described leading to the identification of compounds with optimized in vitro pharmacological and in vitro ADME profiles. In vivo activity has been demonstrated in animal models of food intake and depression.

Topics: Animals; Chemistry, Pharmaceutical; Depression; Disease Models, Animal; Drug Design; Feeding Behavior; Hydantoins; Kinetics; Melanins; Models, Biological; Models, Chemical; Models, Molecular; Receptors, Pituitary Hormone; Receptors, Somatostatin; Structure-Activity Relationship

The aim of this study was to validate melanin-concentrating hormone (MCH)-1 receptor antagonism as a potential treatment of mood disorders. We attempted to replicate the effects previously reported with SNAP-7941 and expanded the investigation to three other orally bioavailable MCH-1 receptor antagonists with good brain penetration. SNAP-7941 (3-30 mg/kg, i.p.) and T-226296 (5-60 mg/kg, p.o.) (+/- racemate), were evaluated in the rat forced swim and mouse tail suspension tests. (+)SNAP-7941 (3-10 mg/kg, p.o.) was also tested in a modified 5-min rat forced swim protocol as previously reported. A-665798 (3-30 mg/kg, p.o.) and A-777903 (3-30 mg/kg, p.o.) were tested in mouse tail suspension and rat Vogel tests. None of the compounds showed meaningful efficacy in the paradigms tested. The lack of efficacy with four structurally different MCH-1 receptor antagonists does not support a role for therapeutic treatment of depression/anxiety via this mechanism of action.

Topics: Analysis of Variance; Animals; Anxiety; Benzopyrans; Biphenyl Compounds; Conflict, Psychological; Depressive Disorder; Disease Models, Animal; Hindlimb Suspension; Indazoles; Male; Mice; Mice, Inbred BALB C; Motor Activity; Naphthalenes; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Somatostatin; Swimming