Molecular and structural insights into the 5-HT2C receptor as a therapeutic target for substance use disorders

Maleesha Ubhayarathna; Christopher J Langmead; Natalie A Diepenhorst; Gregory D Stewart

doi:10.1111/bph.16233

Molecular and structural insights into the 5-HT_2C receptor as a therapeutic target for substance use disorders

Br J Pharmacol. 2023 Sep 7. doi: 10.1111/bph.16233. Online ahead of print.

Authors

Maleesha Ubhayarathna^{1

2}, Christopher J Langmead^{1

2

3}, Natalie A Diepenhorst^{1

2}, Gregory D Stewart^{1

2

3}

Affiliations

¹ Drug Discovery Biology and Neuroscience & Mental Health Therapeutic Program Area, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
² ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
³ Neuromedicines Discovery Centre, Monash University, Parkville, Australia.

PMID: 37679998
DOI: 10.1111/bph.16233

Abstract

Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological function of the serotonin 2C receptor (5-HT_2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5-HT₂ receptors, have indicated potential for the treatment of SUD, implicating the 5-HT_2C receptor. The modern psychedelic movement has rekindled interest in the 5-HT_2C receptor, resulting in many new studies, especially structural analyses. This review explores the structural, molecular and cellular mechanisms governing 5-HT_2C receptor function in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration.

Keywords: 5-HT; 5-HT2C receptor; GPCR; SUDs; cell signalling; drug discovery.

Publication types

Review