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The MCH 1 receptor, an anti‐obesity target, is allosterically inhibited by 8‐methylquinoline derivatives possessing subnanomolar binding and long residence times
Author(s) -
Sakurai T,
Ogawa K,
Ishihara Y,
Kasai S,
Nakayama M
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12529
Subject(s) - allosteric regulation , receptor , chemistry , pharmacology , melanin concentrating hormone , cricetulus , mechanism of action , antagonism , allosteric modulator , biophysics , biochemistry , stereochemistry , chinese hamster ovary cell , biology , in vitro , neuropeptide
Background and Purpose Melanin‐concentrating hormone receptor 1 ( MCH 1 receptor) antagonists are being considered as anti‐obesity agents. The present study reports a new class of MCH 1 receptor antagonists with an 8‐methylquinoline scaffold. The molecular mechanism of MCH 1 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 G α i and G α q , 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 MCH 1 receptor blocker with a low K off value. Conclusion and Implications This is the first time that a slowly dissociating negative allosteric modulator of the MCH 1 receptor has been demonstrated to inhibit the numerous signalling pathways of this receptor. The characteristics of MQ1 are superior and distinct from previously reported MCH 1 receptor antagonists, making members of this chemotype attractive as drug candidates.