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<i>R</i>,5<i>S</i>,9<i>R</i>)-2-phenethyl-9-vinyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol (<b>DC-1-76.2</b>), 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 [³⁵S]GTPγS functional assay. This amide, <b>5</b>, 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, <b>5</b>, as a functionally selective, low-efficacy, and low-potency MOR agonist with a relatively short duration of action in vivo. Modification of the <i>N</i>-phenethyl substituent in <b>DC-1-76.2</b> gave a number of highly interesting partial agonists and the unexpectedly potent antagonist, <b>17</b>. The results of molecular docking and binding free energy calculations for <b>DC-1-76.2</b> and <b>17</b> 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.