Structure-Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ-Opioid Receptor.

ABSTRACT: The US faces an unprecedented surge in fatal drug overdoses. Naloxone, the only antidote for opiate overdose, competes at the mu opioid receptor (μOR) orthosteric site. Naloxone struggles against fentanyl-class synthetic opioids that now cause ∼80% of deaths. Negative allosteric modulators (NAMs) targeting secondary sites may noncompetitively downregulate μOR activation. (-)-Cannabidiol ((-)-CBD) is a candidate μOR NAM. To explore its therapeutic potential, we evaluated the structure-activity relationships among CBD analogs to identify NAMs with increased potency. Using a cyclic AMP assay, we characterize reversal of μOR activation by 15 CBD analogs, several of which proved more potent than (-)-CBD. Comparative docking investigations suggest that potent compounds interact with a putative a

SUBMITTER: Bosquez-Berger T 

PROVIDER: S-EPMC11299522 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature