The Muscarinic Acetylcholine Receptor M₅: Therapeutic Implications and Allosteric Modulation

Abstract

The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) was the most recent mAChR to be cloned and has since emerged as a potential therapeutic target for a number of indications. Early studies with knockout animals have provided clues to the receptor’s role in physiological processes related to Alzheimer’s disease, schizophrenia, and addiction, and until recently, useful subtype-selective tools to further probe the pharmacology of M5 have remained elusive. Small-molecule allosteric modulators have since gained traction as a means by which to selectively examine muscarinic pharmacology. This review highlights the discovery and optimization of M5 positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs).

Acute Negative Allosteric Modulation of M5 Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect on Antinociception

“…Over the last decade, we have made tremendous progress in discovering subtypeselective mAChR allosteric modulators that do not target the orthosteric binding site of ACh, but instead act at more topographically distinct allosteric sites to provide unprecedented selectivity for the M 5 mAChR. 25 This strategy has led to the discovery of the first systemically active M 5 negative allosteric modulator (NAM) ML375 [26][27][28] with suitable pharmacokinetic properties for investigating the role of M 5 receptors in preclinical models of addiction. In previous studies, functional antagonism of the M 5 mAChR subtype by ML375 attenuated cocaine and ethanol self-administration in rats at doses that did not affect non-drug related behaviors or general motor function.…”

Crystal structure of the M5 muscarinic acetylcholine receptor

“…Individual mAChR subtypes have long been pursued as drug targets for a range of CNS disorders, and recent studies have begun to validate the M 5 mAChR as a novel target for the treatment of drug addiction (4, 41). In this study, we have determined a high-resolution crystal structure of the M 5 mAChR, thus allowing the first subtype-wide comparison for any aminergic GPCR subfamily.…”

“…Given the involvement of mAChRs in such a wide range of fundamental physiological processes, they have long been valued as targets for novel therapeutics, in particular the central M 1 and M 4 mAChRs, which have garnered attention due to their involvement in cognition and memory (2). In contrast, relatively less is known about the M 5 mAChR subtype, which represents less than 2% of the total CNS mAChR population (3, 4). Despite its low level of expression, this receptor plays a vital role in the mesolimbic reward pathway due to its presence on dopaminergic neurons of the ventral tegmental area (VTA) (5–8).…”

Crystal structure of the M 5 muscarinic acetylcholine receptor

“…Given the involvement of mAChRs in such a wide range of fundamental physiological processes, they have long been valued as targets for novel therapeutics, in particular the central M 1 and M 4 mAChRs, which have garnered attention due to their involvement in cognition and memory (2). In contrast, relatively less is known about the M 5 mAChR subtype, which represents less than 2% of the total CNS mAChR population (3, 4). Despite its low level of expression, this receptor plays a vital role in the mesolimbic reward pathway due to its presence on dopaminergic neurons of the ventral tegmental area (5–8).…”