Novel 5-Phenylmorphans as Opioid Receptor Antagonists: Synthesis, Structure-Activity Relationship, Biological Evaluation and Computational Modeling

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.