2. Academic Validation
  3. Transformation of a Potent C9-Substituted Phenylmorphan into MOR Partial Agonists with Improvement of Metabolic Stability: An In Vitro, In Vivo, and In Silico Study

Transformation of a Potent C9-Substituted Phenylmorphan into MOR Partial Agonists with Improvement of Metabolic Stability: An In Vitro, In Vivo, and In Silico Study

  • ACS Chem Neurosci. 2025 Jun 4;16(11):2110-2127. doi: 10.1021/acschemneuro.5c00211.
Delmis E Hernandez 1,  Dan Luo 2,  Thomas E Prisinzano 2,  S Stevens Negus 3,  Nima Nassehi 3,  Dana E Selley 3,  Pranav Shah 4,  Rintaro Kato 4,  Xin Xu 4,  Carmine Talarico 5,  Davide Graziani 5,  Andrea R Beccari 5,  Arthur E Jacobson 1,  Kenner C Rice 1,  Agnieszka Sulima 1
Affiliations

Affiliations

  • 1 Department of Health and Human Services, Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9800 Medical Center Drive, Bethesda, Maryland 20892-3373, United States.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, Kentucky 40536, United States.
  • 3 Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay Street, Richmond, Virginia 23298, United States.
  • 4 Department of Health and Human Services, Drug Metabolism and Pharmacokinetics Core, National Center for Advancing Translational Sciences, National Institutes of Health, 9808 Medical Center Drive, Rockville, Maryland 20850, United States.
  • 5 EXSCALATE-Dompé Farmaceutici SpA, Via Tommaso De Amicis 95, 80131 Napoli, Italy.
PMID: 40393055 DOI: 10.1021/acschemneuro.5c00211
Abstract

Replacement of the phenolic hydroxy in 3-((1R,5S,9R)-2-phenethyl-9-vinyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol (DC-1-76.2), a potent efficacious MOR agonist, with an amide bioisosteric moiety provided a MOR partial agonist with morphine-like potency in the forskolin-induced cAMP accumulation assay and in the [35S]GTPγS functional assay. This amide, 5, had superior metabolic stability in comparison to its precursor in human and mouse liver microsomes. However, in an antinociception study, an assay of pain-depressed locomotion in mice, it was found to possess shorter antinociceptive activity than its precursor. The in vitro and in vivo data enabled the characterization of amide, 5, as a functionally selective, low-efficacy, and low-potency MOR agonist with a relatively short duration of action in vivo. Modification of the N-phenethyl substituent in DC-1-76.2 gave a number of highly interesting partial agonists and the unexpectedly potent antagonist, 17. The results of molecular docking and binding free energy calculations for DC-1-76.2 and 17 provided details about their receptor interactions and supported their functional roles. Several analogs synthesized were found to have sufficient potency in vitro to warrant further study.

Keywords

agonists; antagonists; bioisosteres; mu opioid receptor (MOR); opioid use disorder (OUD).

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