Role of efficacy as a determinant of locomotor activation by mu ‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

AbstractLow-efficacy mu-opioid receptor (MOR) agonists represent promising therapeutics, but existing compounds (e.g., buprenorphine, nalbuphine) span a limited range of low MOR efficacies and have poor MOR selectivity. Accordingly, new and selective low-efficacy MOR agonists are of interest. A novel set of chiral C9-substituted phenylmorphans has been reported to display improved MOR selectivity and a range of high-to-low MOR efficacies under other conditions; however, a full opioid receptor binding profile for these drugs has not been described. Additionally, studies in mice will be useful for preclinical characterization of these novel compounds, but the pharmacology of these drugs in mice has also not been examined. Accordingly, the present study characterized the binding selectivity and in vitro efficacy of these compounds using assays of opioid receptor binding and ligand-stimulated [35S]GTP ɣS binding. Additionally, locomotor effects were evaluated as a first step for in vivo behavioral assessment in mice. The high-efficacy MOR agonist and clinically effective antidepressant tianeptine was included as a comparator. In binding studies, all phenylmorphans showed improved MOR selectivity relative to existing lower-efficacy MOR agonists. In the ligand-stimulated [35S]GTP ɣS binding assay, seven phenylmorphans had graded levels of sub-buprenorphine MOR efficacy. In locomotor studies, the compounds again showed graded efficacy with a rapid onset and ≥1 h duration of ef...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research