Document Detail

The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries.
MedLine Citation:
PMID:  19041642     Owner:  NLM     Status:  MEDLINE    
Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits potent orexigenic activity. In rodents, it exerts its actions by interacting with one receptor, MCH(1) receptor which is expressed in many parts of the central nervous system (CNS). To study the physiological implications of the MCH system, we need to be able to block it locally and acutely. This necessitates the use of MCH(1) receptor antagonists. While MCH(1) receptor antagonists have been previously reported, they are mainly not accessible to academic research. We apply here a strategy that leads to the isolation of a high affinity and selective MCH(1) receptor antagonist amenable to in vivo analyses without further chemical modifications. This antagonist, TPI 1361-17, was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL) totaling more than eight hundred thousand compounds in conditions that allow for the identification of only high-affinity compounds. TPI 1361-17 exhibited an IC(50) value of 6.1 nM for inhibition of 1 nM MCH-induced Ca(2+) mobilization and completely displaced the binding of [(125)I] MCH to rat MCH(1) receptor. TPI 1361-17 was found specific, having no affinity for a variety of other G-protein coupled receptors and channels. TPI 1361-17 was found active in vivo since it blocked MCH-induced food intake by 75%. Our results indicate that TPI 1361-17 is a novel and selective MCH(1) receptor antagonist and is an effective tool to study the physiological functions of the MCH system. These results also illustrate the successful application of combinatorial library screening to identify specific surrogate antagonists in an academic setting.
Hiroshi Nagasaki; Shinjae Chung; Colette T Dooley; Zhiwei Wang; Chunying Li; Yumiko Saito; Stewart D Clark; Richard A Houghten; Olivier Civelli
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-11-17
Journal Detail:
Title:  European journal of pharmacology     Volume:  602     ISSN:  1879-0712     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-12     Completed Date:  2009-03-30     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  194-202     Citation Subset:  IM    
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MeSH Terms
Cell Line
Combinatorial Chemistry Techniques*
Cytoskeletal Proteins / antagonists & inhibitors*,  metabolism
Drug Evaluation, Preclinical
Eating / drug effects
Ethylenethiourea / analogs & derivatives*,  chemistry,  pharmacology
Guanidines / chemistry,  pharmacology*
Motor Activity / drug effects
Rats, Sprague-Dawley
Substrate Specificity
Taste / drug effects
Thiourea / chemistry,  pharmacology
Grant Support
DK 063001/DK/NIDDK NIH HHS; MH 060231/MH/NIMH NIH HHS; R01 DK063001/DK/NIDDK NIH HHS; R01 DK063001-01/DK/NIDDK NIH HHS; R01 DK063001-02/DK/NIDDK NIH HHS; R01 DK063001-03/DK/NIDDK NIH HHS; R01 DK063001-04/DK/NIDDK NIH HHS; R01 MH060231/MH/NIMH NIH HHS; R01 MH060231-01/MH/NIMH NIH HHS; R01 MH060231-02/MH/NIMH NIH HHS; R01 MH060231-03/MH/NIMH NIH HHS; R01 MH060231-04/MH/NIMH NIH HHS; R01 MH060231-05A2/MH/NIMH NIH HHS; R01 MH060231-06/MH/NIMH NIH HHS; R01 MH060231-06S1/MH/NIMH NIH HHS; R01 MH060231-07/MH/NIMH NIH HHS; R01 MH060231-08/MH/NIMH NIH HHS; R01 MH060231-09/MH/NIMH NIH HHS
Reg. No./Substance:
0/Cytoskeletal Proteins; 0/Guanidines; 0/Mch1 protein, rat; 0/N-(3-(1-(2-(benzylamino)-1-methylethyl)-3-(2-(3-fluorophenyl)ethyl)-2-thioxoimidazolidin-4-yl)propyl)guanidine; 24FOJ4N18S/Ethylenethiourea; GYV9AM2QAG/Thiourea

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