The synthesis and pharmacology of (&)-trans-3,4-dichloro-N-methyl-N- [5-methoxy-2-(pyrrolidin-1 -yl)-1,2,3,4-tetrahydronaphthalen-1 -yl]benzeneacetamide methanesulfonate (DuP 747) a novel kappa agonist analgesic, are described.The presence of mu, kappa, and delta opioid receptors in the central and peripheral nervous system of many mammalian species has been convincingly demonstrated since the concept of multiple opioid receptors was propounded about sixteen years ago. Of these, the kappa receptor seems to be unique in that agonists that selectively bind to it are postulated to be potent centrally acting analgesics bereft of the undesirable narcotic side effects and addiction liability elicited by the mu selective agonists.In our ongoing search for new and potent analgesics, we had, a few years ago, initiated a program directed toward the design and synthesis of compounds that would be selective agonists of the kappa receptor. At that time, the only selective kappa agonists described in the literature were tifluadom (1) and U-50,488 (2). Ethylketocyclazocine (3a) and bremazocine (3b), though endowed with a high degree of affinity to the kappa receptor, are not selective to that receptor alone in that they exhibit an equal preference to the mu receptor as well - the former as an agonist and the latter as an antagonist.Since the 2-aminotetralin unit of 4, which has been reported to be a potent narcotic analgesic, is a part of morphine and, hence, of ethylketocyclazocine (3a) molecular framework, it was of interest to combine the structural features of 2 and 4 into a single unit as 5 or 6 either or both of which could be expected to display kappa agonist specificity and analgesic activity. Accordingly, the racemic trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]benzeneacetamide (5) was synthesized starting with 1,2_dihydronapthalene (7) as outlined in Scheme 1. The epoxide (8) obtained from 7 by oxidation with 3-chloroperoxybenzoic acid, furnished 9 upon treatment with excess of pyrrolidine in ethanol. The aziridinium intermediate (10) formed when (9) was exposed to methanesulfonyl chloride in the presence of triethylamine, was, without isolation, treated with an excess of methylamine in ethanol to yield the diamine (11). Acylation of 11 with 3,4-dichlorophenylacetyl chloride afforded 5 which was isolated and characterized as the hydrochloride. The regio- and stereochemistry assigned to the product (5) was arrived at by detailed NMR analysis and confirmed by single crystal X-ray structure determinations.Our expectations were more than fulfilled when 5 displayed a high degree of kappa selectivity (Table 1) and also elicited potent in viva antinociceptive activity in the mouse and rat phenylquinone writhing antagonism (PQW) tests (Table 2). It was, however, inactive in the rat tail-flick assay which is a test for strong analgesic activity, even when administered subcutaneously.A minor modification of structure 5 led to DuP 747 (19) as the compound of choice for development. A slightly different route was followed for the synthesis of 19 which is also depicted in Scheme 1. Reduction of 5methoxytetralone (12) with sodium borohydride followed by dehydration of the resulting carbinol (13) yielded 5methoxy-3,4 dihydronapthalene (14) which was converted to the bromohydrin (15) by treatment with N-bromosuccinimide in aqueous acetone. When exposed to an excess of pyrrolidine in ethanol, 15 yielded 16 the formation of which can be rationalized by the in situ generation and susequent opening of the corresponding epoxide by the base. Mesylation of 16 furnished the aziridinium intermediate (17) which, without isolation, was converted to the diamine (18) as described earlier. Coupling of 18 with 3,4 dichlorophenylacetic acid in the presence of 1 ,I'-carbonyldiimidazole and treatment of the product with methanesulfonic acid furnished the title compound (19) designated as DuP 747. Its pharmacology is outlined in Tables 1 and 2.DuP 747 (19) is a selective kappa agonist analgesic which elicits antinociceptive response in mice, rats, and dogs by parenteral as well as oral routes of administration. It is as selective as U-50,488 in its affinity to the kappa receptor and is nearly equipotent with morphine against chemically-induced pain in the mouse PQW test (table 2). It is also active against heat and pressure-induced pain in rats (ED50=31 mg/kg for uninflamed paw and 26 mg/kg for inflamed paw, respectively) and electrically stimulated tooth pulp pain in rats and dogs (ED50=3.2 mg/kg and 1.3 mglkg, respectively). Chronic treatment with analgesic doses of DuP 747 produces less tolerance than is achieved by equi-analgesic doses of morphine. DuP 747 is not cross-tolerant to DuP 747 in morphine-tolerant mice and morphine is not cross-tolerant to DuP 747-tolerant mice. Mice treated with a three-day continuous infusion of DuP 747 showed no withdrawal symptoms following abrupt discontinuation of treatment. In cross-dependence tests, it failed to substitute for morphine.In conclusion, we have demonstrated that the fusion of a benzene ring to the cyclohexane ring of U-50,488 in a proper orientation is tolerated well by the kappa receptor leading to a novel series of potent, kappa agonist analgesics of which DuP 747 is the best representative. The results of the detailed study of structure-activity relationship in this series are reported in the following letter.