Targeting muscarinic receptors for the treatment of alcohol use disorders: Opportunities and hurdles for clinical development

Emerging evidence suggests muscarinic acetylcholine receptors represent novel targets to treat alcohol use disorder. In this review, we draw from literature across medicinal chemistry, molecular biology, addiction and learning/cognition fields to interrogate the proposition for muscarinic receptor ligands in treating various aspects of alcohol use disorder, including cognitive dysfunction, motivation to consume alcohol and relapse. In support of this proposition, we describe cholinergic dysfunction in the pathophysiology of alcohol use disorder at a network level, including alcohol-induced adaptations present in both human post-mortem brains and reverse-translated rodent models. Preclinical behavioural pharmacology implicates specific muscarinic receptors, in particular, M-4 and M-5 receptors, as potential therapeutic targets worthy of further interrogation. We detail how these receptors can be selectively targeted in vivo by the use of subtype-selective allosteric modulators, a strategy that overcomes the issue of targeting a highly conserved orthosteric site bound by acetylcholine. Finally, we highlight the intense pharma interest in allosteric modulators of muscarinic receptors for other indications that provide an opportunity for repurposing into the alcohol use disorder space and provide some currently unanswered questions as a roadmap for future investigation.

Automated summary

Emerging evidence suggests muscarinic acetylcholine receptors are potential targets for treating alcohol use disorder. This review integrates findings from medicinal chemistry, molecular biology, addiction, and learning/cognition fields to explore the potential of muscarinic receptor ligands in treating cognitive dysfunction, motivation to consume alcohol, and relapse associated with alcohol use disorder. The dysfunctional role of cholinergic system in alcohol use disorder is discussed, along with the potential therapeutic targets of specific muscarinic receptors, particularly M-4 and M-5 receptors. The use of subtype-selective allosteric modulators is proposed as a strategy to target these receptors, and the potential repurposing of muscarinic receptor modulators for alcohol use disorder is highlighted.