1. Academic Validation
  2. Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors

Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors

  • Mol Pharmacol. 2018 Feb;93(2):157-167. doi: 10.1124/mol.117.109561.
Kathryn E Livingston 1 M Alexander Stanczyk 1 Neil T Burford 1 Andrew Alt 1 Meritxell Canals 1 John R Traynor 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Edward F. Domino Research Center, University of Michigan, Ann Arbor, Michigan (K.E.L., M.A.S., J.R.T.); Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (N.T.B., A.A.); and Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (M.C.).
  • 2 Department of Pharmacology and Edward F. Domino Research Center, University of Michigan, Ann Arbor, Michigan (K.E.L., M.A.S., J.R.T.); Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (N.T.B., A.A.); and Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (M.C.) jtraynor@umich.edu.
Abstract

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.

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