title: Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Toray Industries, Inc., Kanagawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.forename: J
authors.initials: J
authors.lastname: Hayakawa
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: K
authors.initials: K
authors.lastname: Kawai
authors.forename: Y
authors.initials: Y
authors.lastname: Takezawa
authors.forename: H
authors.initials: H
authors.lastname: Matsuura
authors.forename: C
authors.initials: C
authors.lastname: Tajima
authors.forename: T
authors.initials: T
authors.lastname: Endo
mesh_terms: D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009019:Morphinans / Q000138:chemical synthesis* / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820