Structure-Activity Relationships of Pan-Gαq/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators.

ABSTRACT: Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-Gq-coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs). Using a combination of radioligand binding, functional inositol phosphate accumulation assays, receptor alkylation and operational data analysis, we show that most compounds in the series derive their variable potency and selectivity from differential cooperativity at the M1, M3 and M5

SUBMITTER: Berizzi AE 

PROVIDER: S-EPMC6106869 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature