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Pharmacologic evidence for a putative conserved allosteric site on opioid receptors

Livingston, K.E.; Stanczyk, M.A.; Burford, N.T.; Alt, A.; Canals, M.; Traynor, J.R.


K.E. Livingston

M.A. Stanczyk

N.T. Burford

A. Alt

J.R. Traynor


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. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Journal Article Type Article
Acceptance Date Nov 27, 2017
Online Publication Date Jan 12, 2018
Publication Date Feb 1, 2018
Deposit Date Jan 13, 2020
Print ISSN 0026-895X
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 93
Issue 2
Pages 157-167
Keywords bms 986122; bms 986187; delta opiate receptor; kappa opiate receptor; mu opiate receptor; nociceptin receptor; opiate agonist; opiate antagonist; opiate receptor; unclassified drug; allosteric site; animal cell; Article; binding affinity; binding site; co
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