Lack of efficacy of melanin-concentrating hormone-1 receptor antagonists in models of depression and anxiety.
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.
Basso
Ana M
AM
Neuroscience, Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. Ana.basso@abbott.com
Bratcher
Natalie A
NA
Gallagher
Kelly B
KB
Cowart
Marlon D
MD
Zhao
Chen
C
Sun
Minghua
M
Esbenshade
Timothy A
TA
Brune
Michael E
ME
Fox
Gerard B
GB
Schmidt
Martin
M
Collins
Christine A
CA
Souers
Andrew J
AJ
Iyengar
Rajesh
R
Vasudevan
Anil
A
Kym
Philip R
PR
Hancock
Arthur A
AA
Rueter
Lynne E
LE
D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000503:physiopathology / Q000517:prevention & control*; D001578:Benzopyrans / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003220:Conflict, Psychological; D003866:Depressive Disorder / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D019417:Hindlimb Suspension / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000502:physiology; D013550:Swimming
C515241:(1-benzo(1,3)dioxal-5-ylmethyl-piperidines-4-yl)-(5-chloro-1H-indazole-3-yl)-amine; C515240:(4-(1-benzo(1,3)dioxol-5-ylmethyl-piperidine-4-ylamino)-6-chloro-chromen-2-one); D001578:Benzopyrans; D001713:Biphenyl Compounds; D007191:Indazoles; C491209:Mchr1 protein, mouse; D009281:Naphthalenes; D010880:Piperidines; D011743:Pyrimidines; D017481:Receptors, Somatostatin; C464854:SNAP7941; C457679:T-226296