Discovery of a structurally novel opioid κ-agonist derived from 4,5- epoxymorphinan

Abstract

A new type of κ-agonist, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α- epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (1, TRK-820), was discovered 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 κ-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 κ-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 κ-agonist showed neither aversion nor preference in the Conditioned Place Preference test, in spite of the fact that prototypes of κ-agonists (U-50488H derivatives) demonstrated aversion.