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.

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

Citation

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. https://doi.org/10.1124/mol.117.109561

• 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
• DOI: https://doi.org/10.1124/mol.117.109561
• 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
• Public URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85041169717&doi=10.1124%2fmol.117.109561&partnerID=40&md5=ba991a91eb1bcfce83371990e736efde
• Publisher URL: http://molpharm.aspetjournals.org/content/93/2/157/tab-article-info