2. Academic Validation
  3. 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

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

  • J Med Chem. 2020 Jul 23;63(14):7663-7694. doi: 10.1021/acs.jmedchem.0c00503.
Rakesh H Vekariya 1,  Wei Lei 2,  Abhisek Ray 1,  Surendra K Saini 1,  Sixue Zhang 1,  Gabriella Molnar 2,  Deborah Barlow 3,  Kelly L Karlage 2,  Edward J Bilsky 2,  Karen L Houseknecht 3,  Tally M Largent-Milnes 2,  John M Streicher 2,  Subramaniam Ananthan 1
Affiliations

Affiliations

  • 1 Chemistry Department, Southern Research, Birmingham, Alabama 35205, United States.
  • 2 Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.
  • 3 Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine 04005, United States.
PMID: 32530286 DOI: 10.1021/acs.jmedchem.0c00503
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 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 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.

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