N-tetrahydrofurfuryl benzomorphans: comparison of a kappa and an agonist/antagonist analgesic

The N-tetrahydrofurfuryl benzomorphan, MK-2034 is a prototype kappa agonist analgesic. Dehydrogenation and addition of a methyl group into the N-furfuryl side chain (MR-1353) results in a 2-fold decrease in analgesic potency, a 12-fold decrease in affinity for the mu receptor, a 5-fold decrease in affinity for the delta receptor and a 60-fold decrease in affinity for the kappa receptor. Both compounds possess intermediate sodium ratios for 3H-naloxone binding; however, unlike MR-2034, MR-1353 possesses a bell-shaped dose response curve for elevations in striatal dopamine metabolites. These data indicate that MR-1353 is an agonist/antagonist analgesic and suggest that the high kappa affinity of MR-2034 is responsible for the potent analgesia.