8 research outputs found
3â[3â(Phenalkylamino)cyclohexyl]phenols: Synthesis, biological activity, and in silico investigation of a naltrexoneâderived novel class of MORâantagonists
The development of novel ÎŒâopioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3â[3â(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% DAMGOâ induced GTPÎłS stimulation, suggesting that they acted as antagonists. Moreover, ExtraâPrecision Glide and GeneralizedâBorn Surface Area experiments provided useful information on the nature of the ligandâreceptor interactions, indicating a peculiar combination of Câ1 stereochemistry and Nâsubstitutions as feasibly essential for MORâligand complex stability. Interestingly, compound 9 showed the best experimental binding affinity, the highest antagonist activity, and the finest MORâligand complex stability. In silico experiments also revealed that the most promising stereoisomer (1R, 3R, 5S) 9 retained 1,3âcis configuration with phenol ring equatorial oriented. Further studies are needed to better characterize the pharmacodynamics and pharmacokinetic properties of these compounds