Pharmacological Evidence for a Putative Conserved Allosteric Site on Opioid Receptors.

Allosteric modulators of G protein-coupled receptors (GPCRs), 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 (μ-OR). BMS-986187 is a structurally distinct PAM for the delta-opioid receptor (δ-OR) that has been reported to show 100-fold selectivity in promoting δ-OR over μ-OR agonism. Here we use ligand binding and second messenger assays to show that BMS-986187 is actually an effective PAM at μ-OR and at the kappa opioid receptor (κ-OR), but is ineffective at the nociceptin receptor (NOPR). The affinity of BMS-986187 for δ-ORs and κ-ORs is approximately 20-30 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 is able to accommodate structurally diverse molecules. The findings have implications for the development of selective allosteric modulators.