DISCOVERY OF A STRUCTURALLY NOVEL OPIOID KAPPA-AGONIST DERIVED FROM 4,5-EPOXYMORPHINAN

A new type of kappa-agonist, 17-cyclopropylmethyl-3,14 beta-dihydroxy- 4,5 alpha-epoxy-6 ta-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan h ydrochloride (1, TRK-820), was discoverd by a new working hypothesis. The ''message-address concept'' for opioid antagonists and the ''acces sory site'' for general antagonists were applied to design TRK-820. A unique structural feature of TRK-820, which is different from other pr ototypical kappa-opioid receptor agonists, is the existence of the 4,5 -epoxymorphinan structure with a tyrosine-glysine moiety for endogenou s opioid peptides such as dynorphins. TRK-820 exhibited high potency a nd high kappa-selectivity in guinea pig ileum (GPI) and mouse vas defe rens (MVD) preparations. In the mouse acetic-acid-induced writhing mod el and mouse tail flick model of antinociception, TRK-820 was 85-140 t imes more potent than morphine and 85-350 times more potent than U-504 88H. This structurally novel kappa-agonist showed neither aversion nor preference in the Conditioned Place Preference test, in spite of the fact that prototypes of kappa-agonists (U-50488H derivatives) demonstr ated aversion.