Molecular insights into GPCR mechanisms for drugs of abuse.

Opioids, cannabinoids, and psychedelics all act by binding to G protein-coupled receptors (GPCRs), which mediate their inebriating, lethal, and therapeutic effects. Recent structural studies reveal the molecular mechanisms of drugs like fentanyl, tetrahydrocannabinol, and lysergic acid diethylamide at their respective GPCR subtypes. These insights facilitate drug discovery, both for developing treatments to combat substance abuse and for harnessing the therapeutic potential of certain drugs.

Study at a glance

Abstract

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.