Pharmacologic evidence for a putative conserved allosteric site on opioid receptors

Allosteric modulators of G protein–coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the μ -opioid receptor ( µ -OR). BMS-986187 is a structurally distinct PAM for the δ -opioid receptor ( δ -OR) that has been reported to exhibit 100-fold selectivity in promoting δ -OR over μ -OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the μ -OR and at the κ -opioid receptor ( κ -OR), but it is ineffective at the nociceptin receptor. The affinity of BMS-986187 for δ -ORs and κ -ORs is approximately 20- to 30-fold higher than for μ -ORs, determined using an allosteric ternary complex model. Moreover, we provide evidence, using a silent allosteric modulator as an allosteric antagonist, that BMS-986187 and BMS-986122 bind to a similar region on all three traditional opioid receptor types ( µ -OR, δ -OR, and κ -OR). In contrast to the dogma surrounding allosteric modulators, the results indicate a possible conserved allosteric binding site across the opioid receptor family that can accommodate structurally diverse molecules. These findings have implications for the development of selective allosteric modulators.