The MCH(1) receptor, an anti-obesity target, is allosterically inhibited by 8-methylquinoline derivatives possessing subnanomolar binding and long residence times.

ABSTRACT:

Background and purpose

Melanin-concentrating hormone receptor 1 (MCH1 receptor) antagonists are being considered as anti-obesity agents. The present study reports a new class of MCH1 receptor antagonists with an 8-methylquinoline scaffold. The molecular mechanism of MCH1 receptor blockade by these antagonists was examined.

Experimental approach

The pharmacological properties of the 8-methylquinolines as exemplified by MQ1 were evaluated by use of multiple biophysical and cell-based functional assays.

Key results

Multiple signalling pathways for Gαi and Gαq , and β-arrestin were inhibited by MQ1. Furthermore, MQ1 produced an insurmountable antagonism, causing a rightward shift of the curve for concentration-dependent binding of MCH along with a progressive reduction of

SUBMITTER: Sakurai T 

PROVIDER: S-EPMC3952805 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature