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A new type of kappa-agonist, 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4,5 alpha-epoxy-6 beta-[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 kappa-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 kappa-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 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) demonstrated aversion.

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Because there are few efficacious medications for drug dependence, many clinical trials are being conducted in earnest to find such medications. Considerable evidence has shown that opioid kappa receptor agonists attenuate several behavioral responses induced by drugs of abuse. Although this raises the possibility that opioid kappa receptor agonists may be useful for the treatment of drug dependence on drugs of abuse, it has been previously reported that treatment with selective opioid kappa receptor agonists causes a psychotomimetic effect and dysphoria both in clinical studies and experimental animal models. As a result, we found the novel opioid kappa receptor agonist TRK-820, another chemical class of opioid kappa receptor agonist that has a morphinan scaffold unlike prototypical opioid kappa receptor agonists, by application of a modified message-address concept. TRK-820 showed high selectivity for an opioid kappa receptor, and strong agonistic activity in both in vitro and in vivo experiments. Like other opioid kappa receptor agonists, TRK-820 could markedly suppress the rewarding effects induced by morphine and cocaine and the discriminative stimulus effect of cocaine. Furthermore, TRK-820 attenuated the mecamylamine-precipitated nicotine-withdrawal aversion in a conditioned place preference paradigm. It is worthwhile to note that unlike prototypical opioid kappa receptor agonists, TRK-820 failed to produce a significant place aversion in rodents at doses that were sufficient to produce significant antinociception. Taken together, these findings indicate that TRK-820 may be useful for the treatment of drug dependence without any aversive effects.

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