LAUSR

The development of novel μ‐opioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3‐[3‐(phenalkylamino)cyclohexyl]phenol analogs were designed, synthesized, and evaluated for their MOR antagonist activity in vitro and in silico. At the highest concentrations, the compounds decreased by 52% to 75% DAMGO‐induced GTPγS stimulation, suggesting that they acted as antagonists. Moreover, Extra‐Precision Glide and Generalized‐Born Surface Area experiments provided useful information on the nature of the ligand–receptor interactions, indicating a peculiar combination of C‐1 stereochemistry and N‐substitutions as feasibly essential for MOR–ligand complex stability. Interestingly, compound 9 showed the best experimental binding affinity, the highest antagonist activity, and the finest MOR–ligand complex stability. In silico experiments also revealed that the most promising stereoisomer (1R, 3R, 5S) 9 retained 1,3‐cis configuration with phenol ring equatorial oriented. Further studies are needed to better characterize the pharmacodynamics and pharmacokinetic properties of these compounds.