Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

Z Vuckovic; J Wang; V Pham; JI Mobbs; MJ Belousoff; A Bhattarai; WAC Burger; G Thompson; M Yeasmin; V Nawaratne; K Leach; ET van der Westhuizen; E Khajehali; YL Liang; A Glukhova; D Wootten; CW Lindsley; A Tobin; P Sexton; R Danev; C Valant; Y Miao; A Christopoulos; DM Thal

Journal article

Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

Z Vuckovic, J Wang, V Pham, JI Mobbs, MJ Belousoff, A Bhattarai, WAC Burger, G Thompson, M Yeasmin, V Nawaratne, K Leach, ET van der Westhuizen, E Khajehali, YL Liang, A Glukhova, D Wootten, CW Lindsley, A Tobin, P Sexton, R Danev Show all

Elife | Published : 2023

DOI: 10.7554/eLife.83477

Abstract

Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular-level understanding of the general principles that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M4 muscarinic acetylcholine receptor (M4 mAChR) is a validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders. In this study, we rigorously quantified the affinity, efficacy, and magnitude of modulation of two different positive allosteric modulators, LY2033298 (LY298) and VU0467154 (VU154), combined with the endogenous agonist acetylcholine (ACh) or ..

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