Novel 5-Phenylmorphans as Opioid Receptor Antagonists: Synthesis, Structure-Activity Relationship, Biological Evaluation and Computational Modeling
7 affiliations
- 1Drug 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, Department of Health and Human Services, 9800 Medical Center Drive, Rockville, MD 20850-3373, USA
- 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, KY 40536, USA
- 3Drug Metabolism and Pharmacokinetics Core, National Center for Advancing Translational Sciences, National Institutes of Health, Department of Health and Human Services, 9808 Medical Center Drive, Rockville, MD 20850-3375, USA
- 4Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA 23298, USA
- 5Department of Pathophysiology and Integrative Biomedical Sciences and the Dalton Cardiovascular Research Center, University of Missouri, 1500 Research Park Dr., Columbia, MO 65211, USA
- 6EXSCALATE—Dompé Farmaceutici SpA, via Tommaso De Amicis 95, 80131 Napoli, Italy
- 7Radiochemistry and Preclinical Research Unit, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9000 Rockville Pike, Bethesda, MD 20892-1013, USA
Abstract
The widespread emergence of ultra-potent synthetic opioids in illicit drug supplies and the limited effectiveness of naloxone in reversing certain synthetic opioid overdoses highlight the urgent need for potent high-affinity opioid antagonists. This study describes an improved synthetic approach and structure-activity relationship (SAR) study of N-substituted analogs of a potent and active MOR antagonist, 3-((1S,5R,9R)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol ((1S,5R,9R)-1). Pharmacological activity of the synthesized compounds at mu (MOR), delta (DOR), and kappa (KOR) receptors was assessed via a cAMP accumulation assay, and metabolic stability was determined in a microsomal stability assay. Selected compounds underwent additional evaluation in a competition binding assay at the opioid receptors. We identified a 3,5-dichloro analog, 9w, that demonstrated superior MOR potency relative to naloxone in the cAMP assay and increased metabolic stability by 3-fold in comparison to (1S,5R,9R)-1, warranting further evaluation. Notably, no measurable MOR activity was detected for an N-cyclopropylmethyl analog, 9d. Docking and binding free energy analyses identified key differences in receptor engagement that may underlie its inactivity relative to the potent antagonist (1S,5R,9R)-1. This study describes key structural features governing opioid receptor activity and metabolic stability in N-substituted C9-methyl 5-phenylmorphans and informs our future design of MOR antagonists with improved pharmacological profiles.
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BibTeX
@article{hasanpour2026novel,
title = {{Novel 5-Phenylmorphans as Opioid Receptor Antagonists: Synthesis, Structure-Activity Relationship, Biological Evaluation and Computational Modeling}},
author = {Zahra Hasanpour and Dan Luo and Thomas E. Prisinzano and Pranav Shah and Dana E. Selley and James C. Gillespie and Laurel A. Grisanti and Carmine Talarico and Davide Graziani and Xin Xu and Andrea R. Beccari and Kun-Eek Kil and Sung Won Kim and Arthur E. Jacobson and Kenner C. Rice and Agnieszka Sulima},
journal = {Molecules (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/molecules31193508},
url = {https://europepmc.org/article/PMC/PMC13667200},
note = {CC BY},
}
RIS
TY - JOUR
TI - Novel 5-Phenylmorphans as Opioid Receptor Antagonists: Synthesis, Structure-Activity Relationship, Biological Evaluation and Computational Modeling
AU - Zahra Hasanpour
AU - Dan Luo
AU - Thomas E. Prisinzano
AU - Pranav Shah
AU - Dana E. Selley
AU - James C. Gillespie
AU - Laurel A. Grisanti
AU - Carmine Talarico
AU - Davide Graziani
AU - Xin Xu
AU - Andrea R. Beccari
AU - Kun-Eek Kil
AU - Sung Won Kim
AU - Arthur E. Jacobson
AU - Kenner C. Rice
AU - Agnieszka Sulima
PY - 2026
DA - 2026/10/01
JO - Molecules (Basel, Switzerland)
DO - 10.3390/molecules31193508
UR - https://europepmc.org/article/PMC/PMC13667200
AB - The widespread emergence of ultra-potent synthetic opioids in illicit drug supplies and the limited effectiveness of naloxone in reversing certain synthetic opioid overdoses highlight the urgent need for potent high-affinity opioid antagonists. This study describes an improved synthetic approach and structure-activity relationship (SAR) study of N-substituted analogs of a potent and active MOR antagonist, 3-((1S,5R,9R)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol ((1S,5R,9R)-1). Pharmacological activity of the synthesized compounds at mu (MOR), delta (DOR), and kappa (KOR) receptors was assessed via a cAMP accumulation assay, and metabolic stability was determined in a microsomal stability assay. Selected compounds underwent additional evaluation in a competition binding assay at the opioid receptors. We identified a 3,5-dichloro analog, 9w, that demonstrated superior MOR potency relative to naloxone in the cAMP assay and increased metabolic stability by 3-fold in comparison to (1S,5R,9R)-1, warranting further evaluation. Notably, no measurable MOR activity was detected for an N-cyclopropylmethyl analog, 9d. Docking and binding free energy analyses identified key differences in receptor engagement that may underlie its inactivity relative to the potent antagonist (1S,5R,9R)-1. This study describes key structural features governing opioid receptor activity and metabolic stability in N-substituted C9-methyl 5-phenylmorphans and informs our future design of MOR antagonists with improved pharmacological profiles.
SN - 1420-3049
ER -