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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.


Livingston, K., Stanczyk, M., Burford, N., Alt, A., Canals, M., & Traynor, J. (2018). Pharmacologic evidence for a putative conserved allosteric site on opioid receptors. Molecular Pharmacology, 93(2), 157-167.

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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