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 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.

Organocatalytic Enantioselective Syntheses of Flavonoids and Cannabinoids

“…Some flavonoid subgroups have been ignored by the organocatalytic community, such as pterocarpans [61] . Also, the recent discoveries that cannabidiol ( 53 ) analogs can interact with μ‐opioid receptors [62] and have the potential to treat morphine induced addictions [63] are proof that new enantioselective synthetic methodologies capable to provide structural diversity around the cannabinoid‐core (hexahydro‐6 H ‐benzo[ c ]chromene) ( B ) are still needed.…”

Pharmacological and morphological features and socioeconomic aspects of cannabidiol: A literature review

“…The main effect of CB1 and CB2 receptor antagonism is to reduce the binding capacity of tetrahydrocannabinol (THC) and its related isomers [13]. T. Bosquez-Berger et al [14] also studied its ability to exhibit partially antagonistic properties to serotonin receptors. Cannabidiol is also an allosteric opioid receptor modulator.…”

Cannabidiol at Nanomolar Concentrations Negatively Affects Signaling through the Adenosine A2A Receptor

“…In fact, CBD was long ago identified as an agonist of the 5-HT 1A R (with low potency, in the micromolar range) [14]. Recently, Bosquez-Berger et al have convincingly shown that CBD is an allosteric modulator of the µ-opioid receptor [15]. A list of potential receptor targets of CBD was provided in a 2015 review paper in which the A 2A R was not included [16].…”