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.

ABSTRACT: Replacement of the phenolic hydroxy in 3-((1R,5S,9R)-2-phenethyl-9-vinyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol (DC-1-76.2), 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, 5, 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, 5, as a functionally selective, low-efficacy, and low-potency

SUBMITTER: Hernandez DE 

PROVIDER: S-EPMC12136991 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature