A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Sep 10

PMID 34505767

Citations 19

Authors

Soumen Chakraborty

Jeffrey F DiBerto

Abdelfattah Faouzi

Sarah M Bernhard

Anna M Gutridge

Steven Ramsey

Yuchen Zhou

Davide Provasi

Nitin Nuthikattu

Rahul Jilakara

Melissa N F Nelson

Wesley B Asher

Shainnel O Eans

Lisa L Wilson

Satyanarayana M Chintala

Marta Filizola

Richard M van Rijn

Elyssa B Margolis

Bryan L Roth

Jay P McLaughlin

Tao Che

Dalibor Sames

Jonathan A Javitch

Susruta Majumdar

Affiliations

Soon will be listed here.

Abstract

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH group with phenyl (), methyl (), or 3'-furanyl [ ()] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology. In assays limiting MOR reserve, the G-protein efficacy of all three was comparable to buprenorphine. () showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning in mice. These results suggest the possibility of activating MOR minimally (G-protein ≈ 10%) in cell lines while yet attaining maximal antinociception with reduced opioid liabilities.

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