Ring-constrained orvinols as analogs of buprenorphine: Differences in opioid activity related to configuration of C-20 hydroxyl group

The relative positions of the C-20 substituents in buprenorphine, particula rly the hydroxyl group, have been implicated in its actions as a partial mu -agonist and a kappa-antagonist. This hypothesis has been examined by the s ynthesis and pharmacological characterization of five orvinols in which the C-20 carbon atom of buprenorphine is constrained in a five-membered ring, fixing the hydroxyl group above (beta) or below (alpha) the plane of the ri ng. All five compounds were nonselective in binding assays with similar, lo w nanomolar affinities. The compounds acted as delta-agonists in the mouse vas deferens and kappa-agonists in the myenteric plexus-longitudinal muscle of the guinea pig ileum and in Chinese hamster ovary (CHO) cells expressin g the human kappa-opioid receptor (CHO-hkor). All were lower efficacy mu-ag onists than buprenorphine as measured by the [S-35]guanosine-5'-O-(3-thio)t riphosphate assay in SH-SY5Y cells. The major difference between the isomer s was an 11- to 12-fold higher potency of the beta-OH isomer (BU46) compare d with the alpha-OH isomer (BU47) at the kappa-receptor in the guinea pig i leum and CHO-hkor cells and a somewhat higher efficacy of BU46 in CHO-hkor cells. BU46 and BU47 were evaluated in vivo. BU46 was a full agonist in the mouse writhing assay and antinociception was prevented by norbinaltorphimi ne, showing a kappa-mechanism of action. In contrast, BU47 acted as an anta gonist of mu-, delta-, and kappa- mediated antinociception in the writhing assay. The results show that the configuration of the hydroxyl group is not important in binding affinity at mu-, delta-, or kappa-receptors but does influence kappa- potency and kappa-efficacy, particularly in vivo.