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 mu-opioid receptor (mu-OR). BMS-986187 is a structurally distinct PAM for the delta-opioid receptor (delta-OR) that has been reported to exhibit 100-fold selectivity in promoting mu-OR over mu-OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the mu-OR and at the kappa-opioid receptor (kappa-OR), but it is ineffective at the nociceptin receptor. The affinity of BMS-986187 for delta-ORs and kappa-ORs is approximately 20- to 30-fold higher than for mu-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 (mu-OR, delta-OR, and kappa-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.