title: The MCH(1) receptor, an anti-obesity target, is allosterically inhibited by 8-methylquinoline derivatives possessing subnanomolar binding and long residence times.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The pharmacological properties of the 8-methylquinolines as exemplified by MQ1 were evaluated by use of multiple biophysical and cell-based functional assays.
  
  
  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 the maximal response. The dissociation kinetics for MQ1 were determined from washout experiments as well as by affinity selection-MS. In short, MQ1 was shown to be a slowly dissociating reversible MCH1 receptor blocker with a low Koff value.
  
  
  CONCLUSIONS
  This is the first time that a slowly dissociating negative allosteric modulator of the MCH1 receptor has been demonstrated to inhibit the numerous signalling pathways of this receptor. The characteristics of MQ1 are superior and distinct from previously reported MCH1 receptor antagonists, making members of this chemotype attractive as drug candidates.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakurai
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ishihara
authors.forename: S
authors.initials: S
authors.lastname: Kasai
authors.forename: M
authors.initials: M
authors.lastname: Nakayama
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D011804:Quinolines / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C000592627:4-(cyclopropylmethoxy)-N-(8-methyl-3-(1-(pyrrolidin-1-yl)ethyl)quinolin-7-yl)benzamide; D019440:Anti-Obesity Agents; D001549:Benzamides; C103263:MCHR1 protein, human; D011804:Quinolines; D017481:Receptors, Somatostatin; C057609:8-methylquinoline
keywords: antagonist; melanin-concentrating hormone receptor 1 (MCH1 receptor); negative allosteric modulator; obesity; slow dissociation; time-dependent inhibition