Transformation of a Potent C9-Substituted Phenylmorphan into MOR Partial Agonists with Improvement of Metabolic Stability: An In Vitro, In Vivo, and In Silico Study.

Replacement of the phenolic hydroxy in 3-((1,5,9)-2-phenethyl-9-vinyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol (), a potent efficacious MOR agonist, with an amide bioisosteric moiety provided a MOR partial agonist with morphine-like potency in the forskolin-induced cAMP accumulation assay and in the [S]GTPγS functional assay. This amide, , had superior metabolic stability in comparison to its precursor in human and mouse liver microsomes. However, in an antinociception study, an assay of pain-depressed locomotion in mice, it was found to possess shorter antinociceptive activity than its precursor. The in vitro and in vivo data enabled the characterization of amide, , as a functionally selective, low-efficacy, and low-potency MOR agonist with a relatively short duration of action in vivo. Modification of the -phenethyl substituent in gave a number of highly interesting partial agonists and the unexpectedly potent antagonist, . The results of molecular docking and binding free energy calculations for and provided details about their receptor interactions and supported their functional roles. Several analogs synthesized were found to have sufficient potency in vitro to warrant further study.