PMID- 19182070
OWN - NLM
STAT- MEDLINE
DCOM- 20090522
LR  - 20200311
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 329
IP  - 2
DP  - 2009 May
TI  - Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for 
      the treatment of obesity and depression.
PG  - 429-38
LID - 10.1124/jpet.108.143362 [doi]
AB  - The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G 
      protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and 
      MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, 
      we evaluated MCHR1 antagonism in preclinical models believed to be predictive of 
      antiobesity and antidepressant activity. Central activity of the selective MCHR1 
      antagonist, GW803430 
      [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one], 
      was evaluated using ex vivo binding with autoradiography. Effective doses of 
      GW803430 (1 and 3 mg/kg p.o.) were correlated with antiobesity activity in a 
      14-day study of diet-induced obese rats. GW803430 was evaluated subsequently for 
      antidepressant-like effects in mice and rats. Acute and subchronic administration 
      reduced immobility time in the mouse forced-swim test at doses of 3 (acute) and 3 
      and 10 (chronic) mg/kg p.o., an effect that was absent in MCHR1(-/-) mice. 
      Combined subeffective doses of GW803430 (0.3 and 1 mg/kg p.o.) and imipramine (5 
      mg/kg) produced a robust antidepressant-like response. The compound was also 
      active in the tail suspension test at a dose of 10 mg/kg p.o. GW803430 (30 mg/kg 
      p.o.) significantly reduced submissive behaviors at weeks 2 and 3, a model of 
      submissive behavior that may predict antidepressant onset. GW803430 decreased 
      marble burying in mice at doses of 3, 10, and 30 mg/kg p.o., an assay that 
      detects anxiolytic-like effects. Thus, GW803430 produces robust antiobesity and 
      antidepressant-like effects in rats and mice at doses that compete for central 
      MCHR1 in vivo. As such, MCHR1 should be considered as a promising target for 
      future drug discovery efforts.
FAU - Gehlert, Donald R
AU  - Gehlert DR
AD  - Neuroscience and Endocrine Discovery Research, Lilly Research Laboratories, Eli 
      Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. 
      gehlert_donald_r@lilly.com
FAU - Rasmussen, Kurt
AU  - Rasmussen K
FAU - Shaw, Janice
AU  - Shaw J
FAU - Li, Xia
AU  - Li X
FAU - Ardayfio, Paul
AU  - Ardayfio P
FAU - Craft, Libbey
AU  - Craft L
FAU - Coskun, Tamer
AU  - Coskun T
FAU - Zhang, Hong Y
AU  - Zhang HY
FAU - Chen, Yanyun
AU  - Chen Y
FAU - Witkin, Jeffrey M
AU  - Witkin JM
LA  - eng
PT  - Journal Article
DEP - 20090130
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 
      (6-(4-chlorophenyl)-3-(3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl)-3H-thieno(3,2-d)pyrimidin-4-one)
RN  - 0 (Anti-Obesity Agents)
RN  - 0 (Antidepressive Agents)
RN  - 0 (MCHR1 protein, rat)
RN  - 0 (Mchr1 protein, mouse)
RN  - 0 (Pyrimidinones)
RN  - 0 (Receptors, Somatostatin)
RN  - 0 (Thiophenes)
SB  - IM
MH  - Animals
MH  - Anti-Obesity Agents/administration & dosage/pharmacology/*therapeutic use
MH  - Antidepressive Agents/administration & dosage/pharmacology/*therapeutic use
MH  - Autoradiography
MH  - Behavior, Animal/drug effects
MH  - Body Weight/drug effects
MH  - Depression/*drug therapy/metabolism/physiopathology/psychology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Motor Activity/drug effects
MH  - Obesity/*drug therapy/metabolism/physiopathology/psychology
MH  - Protein Binding
MH  - Pyrimidinones/administration & dosage/pharmacology/*therapeutic use
MH  - Rats
MH  - Rats, Long-Evans
MH  - Rats, Sprague-Dawley
MH  - Receptors, Somatostatin/*antagonists & inhibitors/genetics
MH  - Social Dominance
MH  - Swimming
MH  - Thiophenes/administration & dosage/pharmacology/*therapeutic use
EDAT- 2009/02/03 09:00
MHDA- 2009/05/23 09:00
CRDT- 2009/02/03 09:00
PHST- 2009/02/03 09:00 [entrez]
PHST- 2009/02/03 09:00 [pubmed]
PHST- 2009/05/23 09:00 [medline]
AID - jpet.108.143362 [pii]
AID - 10.1124/jpet.108.143362 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2009 May;329(2):429-38. doi: 10.1124/jpet.108.143362. Epub 
      2009 Jan 30.