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

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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

We previously identified a pyridomorphinan (6, 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 /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 20 (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.

Original languageEnglish (US)
Pages (from-to)7663-7694
Number of pages32
JournalJournal of Medicinal Chemistry
Volume63
Issue number14
DOIs
StatePublished - Jul 23 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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