A new type of K-agonist, 17-cyclopropylmethyl-3, 14β-dihydroxy-4, 5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (1, TRK-820), was discoverd by a new working hypothesis. The "message-address concept" for opioid antagonists and the "accessory site" for general antagonists were applied to design TRK-820. A unique structural feature of TRK-820, which is different from other prototypical K-opioid receptor agonists, is the existence of the 4, 5-epoxymorphinan structure with a tyrosine-glysine moiety for endogenous opioid peptides such as dynorphins. TRK-820 exhibited high potency and high K-selectivity in guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. In the mouse acetic-acid-induced writhing model and mouse tail flick model of antinociception, TRK-820 was 85-140 times more potent than morphine and 85-350 times more potent than U-50488H. This structurally novel K-agonist showed neither aversion nor preference in the Conditioned Place Preference test, in spite of the fact that prototypes of K-agonists (U-50488H derivatives) demonstrated aversion.