G protein signaling-biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists
Abstract
Analgesic tolerance can result upon chronic use of opioid drugs necessitating dose escalation to treat pain. The biased mu opioid receptor agonist SR-17018 maintains antinociceptive efficacy without evidence of tolerance when given chronically to mice. Here, we show that SR-17018 and related compounds are noncompetitive agonists that stabilize the receptor in an active state that can still be blocked by orthosteric antagonists. We propose that this mode of activation may contribute to the biased agonists' apparent ability to preferentially induce G protein signaling in cellular assays and may underlie the enduring efficacy observed for SR-17018 in vivo.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- November 2021
- DOI:
- 10.1073/pnas.2102178118
- Bibcode:
- 2021PNAS..11802178S