TY - JOUR T1 - Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 157 LP - 167 DO - 10.1124/mol.117.109561 VL - 93 IS - 2 AU - Kathryn E. Livingston AU - M. Alexander Stanczyk AU - Neil T. Burford AU - Andrew Alt AU - Meritxell Canals AU - John R. Traynor Y1 - 2018/02/01 UR - http://molpharm.aspetjournals.org/content/93/2/157.abstract N2 - 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. ER -