Structure–Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ‑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
(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 allosteric pocket to stabilize the inactive μOR conformation.
Finally, these compounds enhance naloxone displacement of fentanyl
from the orthosteric site. Our results suggest that CBD analogs offer
considerable potential for the development of next-generation antidotes
for opioid overdose.