Allostery of atypical modulators at oligomeric G protein-coupled receptors

Abstract

Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M2 muscarinic receptor, allosteric modulators regulate the binding and functional effects of orthosteric ligands through a mix of conformational changes, steric hindrance and electrostatic repulsion transmitted within and between the constituent protomers of an oligomer. Tacrine has been called an atypical modulator because it exhibits positive cooperativity, as revealed by Hill coefficients greater than 1 in its negative allosteric effect on binding and response. Radioligand binding and molecular dynamics simulations were used to probe the mechanism of that modulation in monomers and oligomers of wild-type and mutant M2 receptors. Tacrine is not atypical at monomers, which indicates that its atypical effects are a property of the receptor in its oligomeric state. These results illustrate that oligomerization of the M2 receptor has functional consequences.

Strychnine and its mono- and dimeric analogues: a pharmaco-chemical perspective

“…185 The fact that the orthosteric site is highly conserved throughout the ve mAChRs has prompted the search for subtype-selectivity through ligands that target other receptor regions, and thus mAChRs have historically been model G-protein-coupled receptors when it comes to allosteric modulation. 186,187 5.3.1. Mode of action.…”

“…In contrast, recent years has seen the development of a plethora of novel, potent and highly subtypeselective small-molecule allosteric modulators acting through both the common vestibular site as well as novel allosteric sites in the mAChRs. [186][187][188] In the present review focus will be exclusively on strychnine, brucine and some of their analogues as allosteric mAChR modulators.…”