Abstract
Muscarinic acetylcholine receptors (mAChRs) are prototypical Family A G protein coupled-receptors. The five mAChR subtypes are widespread throughout the periphery and the central nervous system and, accordingly, are widely involved in a variety of both physiological and pathophysiological processes. There currently remains an unmet need for better therapeutic agents that can selectively target a given mAChR subtype to the relative exclusion of others. The main reason for the lack of such selective mAChR ligands is the high sequence homology within the acetylcholine-binding site (orthosteric site) across all mAChRs. However, the mAChRs possess at least one, and likely two, extracellular allosteric binding sites that can recognize small molecule allosteric modulators to regulate the binding and function of orthosteric ligands. Extensive studies of prototypical mAChR modulators, such as gallamine and alcuronium, have provided strong pharmacological evidence, and associated structure-activity relationships (SAR), for a “common” allosteric site on all five mAChRs. These studies are also supported by mutagenesis experiments implicating the second extracellular loop and the interface between the third extracellular loop and the top of transmembrane domain 7 as contributing to the common allosteric site. Other studies are also delineating the pharmacology of a second allosteric site, recognized by compounds such as staurosporine. In addition, allosteric agonists, such as McN-A-343, AC-42 and N-desmethylclozapine, have also been identified. Current challenges to the field include the ability to effectively detect and validate allosteric mechanisms, and to quantify allosteric effects on binding affinity and signaling efficacy to inform allosteric modulator SAR.
Highlights
G protein-coupled receptors (GPCRs) account for 1 - 3% of the human genome, are abundantly expressed throughout the central nervous system (CNS) and periphery, and represent the major targets for approximately 30% of all medicines on the world market
It is recognized that GPCRs possess topographically distinct, allosteric binding sites, and that ligands that bind to these sites offer tremendous potential for more selective and/or effective therapies than conventional orthosteric ligands
N419, V421 and T423 of the M2 Muscarinic acetylcholine receptors (mAChRs) were found to be important in the manifestation of positive cooperativity of strychnine-like modulators [47]. These mutagenesis studies, together with recent homology modeling based on the crystal structure of inactive state bovine rhodopsin [58, 83, 104], have resulted in the consensus view that the common allosteric binding site for the majority of prototypical allosteric M2 mAChR modulators is located at the opening of the orthosteric binding pocket, the latter which is buried further within the TM bundle
Summary
G protein-coupled receptors (GPCRs) account for 1 - 3% of the human genome, are abundantly expressed throughout the central nervous system (CNS) and periphery, and represent the major targets for approximately 30% of all medicines on the world market. In addition to detecting allosteric ligands that modulate orthosteric ligand affinity, these types of equilibrium binding assays can be used to quantify the allosteric effect in terms of the simple ATCM, providing estimates of modulator KB and (Fig. 2).
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