Structure-Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the & mu;-Opioid Receptor

The US faces an unprecedented surge in fatal drug overdoses.Naloxone,the only antidote for opiate overdose, competes at the mu opioid receptor(& mu;OR) orthosteric site. Naloxone struggles against fentanyl-classsynthetic opioids that now cause & SIM;80% of deaths. Negative allostericmodulators (NAMs) targeting secondary sites may noncompetitively downregulate & mu;OR activation. (-)-Cannabidiol ((-)-CBD) is acandidate & mu;OR NAM. To explore its therapeutic potential, weevaluated the structure-activity relationships among CBD analogsto identify NAMs with increased potency. Using a cyclic AMP assay,we characterize reversal of & mu;OR activation by 15 CBD analogs,several of which proved more potent than (-)-CBD. Comparativedocking investigations suggest that potent compounds interact witha putative allosteric pocket to stabilize the inactive & mu;OR conformation.Finally, these compounds enhance naloxone displacement of fentanylfrom the orthosteric site. Our results suggest that CBD analogs offerconsiderable potential for the development of next-generation antidotesfor opioid overdose.