Lack of efficacy of melanin-concentrating hormone-1 receptor antagonists in models of depression and anxiety.

Abstract

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.

• Authors: Ana M Basso, Natalie A Bratcher, Kelly B Gallagher, Marlon D Cowart, Chen Zhao, Minghua Sun, Timothy A Esbenshade, Michael E Brune, Gerard B Fox, Martin Schmidt, Christine A Collins, Andrew J Souers, Rajesh Iyengar, Anil Vasudevan, Philip R Kym, Arthur A Hancock, Lynne E Rueter
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 540 Issue 1-3 Pg. 115-20 (Jul 01 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16765941 (Publication Type: Journal Article)

Chemical References

• (1-benzo(1,3)dioxal-5-ylmethyl-piperidines-4-yl)-(5-chloro-1H-indazole-3-yl)-amine
• (4-(1-benzo(1,3)dioxol-5-ylmethyl-piperidine-4-ylamino)-6-chloro-chromen-2-one)
• Benzopyrans
• Biphenyl Compounds
• Indazoles
• Mchr1 protein, mouse
• Naphthalenes
• Piperidines
• Pyrimidines
• Receptors, Somatostatin
• SNAP7941
• T-226296

Topics

• Analysis of Variance
• Animals
• Anxiety (physiopathology, prevention & control)
• Benzopyrans (pharmacology)
• Biphenyl Compounds (pharmacology)
• Conflict, Psychological
• Depressive Disorder (physiopathology, prevention & control)
• Disease Models, Animal
• Hindlimb Suspension (physiology)
• Indazoles (pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Motor Activity (drug effects)
• Naphthalenes (pharmacology)
• Piperidines (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptors, Somatostatin (antagonists & inhibitors, physiology)
• Swimming