Synthesis and Structure-Activity Relationships of 5'-Aryl-14-alkoxypyridomorphinans: Identification of a μ Opioid Receptor Agonist/δ Opioid Receptor Antagonist Ligand with Systemic Antinociceptive Activity and Diminished Opioid Side Effects

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Jun 13

PMID 32530286

Citations 10

Authors

Rakesh H Vekariya

Wei Lei

Abhisek Ray

Surendra K Saini

Sixue Zhang

Gabriella Molnar

Deborah Barlow

Kelly L Karlage

Edward J Bilsky

Karen L Houseknecht

Tally M Largent-Milnes

John M Streicher

Subramaniam Ananthan

Affiliations

Soon will be listed here.

Abstract

We previously identified a pyridomorphinan (, SRI-22138) possessing a 4-chlorophenyl substituent at the 5'-position on the pyridine and a 3-phenylpropoxy at the 14-position of the morphinan as a mixed μ opioid receptor (MOR) agonist and δ/κ opioid receptor (DOR/KOR) antagonist with potent antinociceptive activity and diminished tolerance and dependence in rodents. Structural variations at the 5'- and 14-positions of this molecule gave insights into the structure-activity relationships for binding and functional activity. Subtle structural changes exerted significant influence, particularly on the ability of the compounds to function as agonists at the MOR. In vivo evaluation identified compound (SRI-39067) as a MOR agonist/DOR antagonist that produced systemically active potent antinociceptive activity in tail-flick assay in mice, with diminished tolerance, dependence/withdrawal, reward liability, and respiratory depression versus morphine. These results support the hypothesis that mixed MOR agonist/DOR antagonist ligands may emerge as novel opioid analgesics with reduced side effects.

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