FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR-DOR Heteromer

Eyup Akgün, Mary M. Lunzer, Defeng Tian, Michael Ansonoff, John Pintar, Daniel Bruce, Jon E. Hawkinson, George L. Wilcox, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

Abstract

This report describes the unique pharmacological profile of FBNTI, a potent DOR antagonist that acts as a MOR agonist via an allosteric mechanism. Binding of FBNTI to opioid receptors expressed in HEK 293 cells revealed a 190-fold greater affinity for DOR (Ki= 0.84 nM) over MOR (Ki= 160 nM). In mice, intrathecal FBNTI produced potent antinociception (ED50= 46.9 pmol/mouse), which was antagonized by selective MOR antagonists (CTOP, β-FNA). Autoantagonism of the MOR agonism by FBNTI was observed above the ED75dose, suggesting antagonism of activated MOR. That FBNTI is devoid of agonism in DOR knockout mice is consistent with allosteric activation of the MOR protomer via FBNTI bound to within a MOR-DOR heteromer. This proposed mechanism is supported by calcium mobilization assays, which indicate that FBNTI selectively activates the MOR-DOR heteromer and functionally antagonizes the MOR protomer at >ED75. The unprecedented mode of MOR activation by FBNTI may be responsible for the lack of tolerance after intrathecal (i.t.) administration. FBNTI was highly effective upon topical administration to the ipsolateral hind paw in the Hargreaves assay (EC50= 0.17 ± 0.08 μM) and without significant contralateral activity, suggesting a lack of systemic exposure.

Original languageEnglish (US)
Pages (from-to)1413-1419
Number of pages7
JournalBiochemistry
Volume60
Issue number18
DOIs
StatePublished - May 11 2021

Bibliographical note

Funding Information:
This work was supported by College of Pharmacy fund of The University of Minnesota.

Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.

Fingerprint

Dive into the research topics of 'FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR-DOR Heteromer'. Together they form a unique fingerprint.

Cite this