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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.<\/jats:p>","DOI":"10.3390\/molecules31193508","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:43:24Z","timestamp":1790880204000},"page":"3508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel 5-Phenylmorphans as Opioid Receptor Antagonists: Synthesis, Structure-Activity Relationship, Biological Evaluation and Computational Modeling"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2286-3574","authenticated-orcid":false,"given":"Zahra","family":"Hasanpour","sequence":"first","affiliation":[{"name":"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, Department of Health and Human Services, 9800 Medical Center Drive, Rockville, MD 20850-3373, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-3165","authenticated-orcid":false,"given":"Dan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-8052","authenticated-orcid":false,"given":"Thomas E.","family":"Prisinzano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranav","family":"Shah","sequence":"additional","affiliation":[{"name":"Drug 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"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Dana E.","family":"Selley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA 23298, 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