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

Autor: Walker LC; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia., Huckstep KL; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia., Becker HC; Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA., Langmead CJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Lawrence AJ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Nov; Vol. 181 (22), pp. 4385-4398. Date of Electronic Publication: 2023 May 01.
DOI: 10.1111/bph.16081
Abstrakt: 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.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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