title: Pharmacological properties of R-84760, a novel kappa-opioid receptor agonist.
abstract: The pharmacological properties of a structurally novel kappa-opioid receptor agonist, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride (R-84760), were examined. In an opioid receptor binding assay with a guinea pig brain membrane fraction, R-84760 showed a 5 times higher affinity for the kappa-opioid receptor than CI-977, the most potent reference kappa-opioid receptor agonist, and selectivity of R-84760 for the kappa-opioid receptor was higher than that of U-69593, a highly selective kappa-opioid receptor agonist. R-84760 was functionally 2.5 times more potent than CI-977 as a kappa-opioid receptor agonist in rabbit vas deferens. Subcutaneously administered R-84760 had an antinociceptive effect in the phenylquinone writhing test in mice and its potency was 5-846 times higher than those of CI-977, U-50488, morphine, pentazocine and butorphanol. On oral administration, R-84760 was 20-2077 times more potent than the same reference drugs. The antinociceptive effect of R-84760 was not antagonized by naloxone in a dose at which naloxone antagonized the effect of morphine, but on the other hand nor-binaltorphimine antagonized the effect of R-84760 at a dose which did not affect the effect of morphine. R-84760 and the reference kappa-opioid receptor agonists produced sedative and diuretic effects in mice with the same order of potency as for the antinociceptive effect. Tolerance to the antinociceptive effect of R-84760 barely developed, and naloxone-induced jumping tests for morphine-like physical dependence of R-84760 gave negative results.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fujibayashi
authors.forename: K
authors.initials: K
authors.lastname: Sakamoto
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Iizuka
mesh_terms: D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000037:antagonists & inhibitors; D001667:Binding, Competitive / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology; D004361:Drug Tolerance; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009270:Naloxone / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D004856:Postural Balance / Q000187:drug effects; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D019966:Substance-Related Disorders / Q000523:psychology; D013843:Thiazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D016227:Benzoquinones; D004232:Diuretics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013843:Thiazines; C091101:R 84760; C029322:phenylbenzoquinone; D009270:Naloxone