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.
Footnotes
- Received June 2, 2017.
- Accepted November 27, 2017.
↵1 Current affiliation: Department of Psychiatry, Genentech Hall, San Francisco, California.
↵2 Current affiliation: Arvinas Inc, New Haven, Connecticut.
This work was supported by National Institutes of Health, National Institute on Drug Abuse Institute [Grants R01 DA39997 and T32 DA007267] and an EDGE Fellowship from the Endowment for the Basic Sciences, University of Michigan.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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