Molecular insights into GPCR mechanisms for drugs of abuse.

Substance abuse is on the rise, and while many people may use illicit drugs mainly due to their rewarding effects, their societal impact can range from severe, as is the case for opioids, to promising, as is the case for psychedelics. Common with all these drugs' mechanisms of action are G protein-coupled receptors (GPCRs), which lie at the center of how these drugs mediate inebriation, lethality, and therapeutic effects. Opioids like fentanyl, cannabinoids like tetrahydrocannabinol, and psychedelics like lysergic acid diethylamide all directly bind to GPCRs to initiate signaling which elicits their physiological actions. We herein review recent structural studies and provide insights into the molecular mechanisms of opioids, cannabinoids, and psychedelics at their respective GPCR subtypes. We further discuss how such mechanistic insights facilitate drug discovery, either toward the development of novel therapies to combat drug abuse or toward harnessing therapeutic potential.
Competing Interests: Conflict of interest D. W. has consulted for Otsuka Pharmaceutical, Longboard Pharmaceuticals and Ocean Bio Ltd on the design of psychedelic-based therapeutics. None of the companies listed herein contributed to the funding or narrative of the manuscript. The other authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)