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

Chem Pharm Bull (Tokyo). 1998 Feb;46(2):366-9. doi: 10.1248/cpb.46.366.


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.

MeSH terms

  • Animals
  • Binding Sites
  • Drug Design
  • Guinea Pigs
  • Male
  • Mice
  • Morphinans / chemical synthesis*
  • Morphinans / pharmacology*
  • Pain Measurement / drug effects
  • Receptors, Opioid, kappa / agonists*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship


  • Morphinans
  • Receptors, Opioid, kappa
  • Spiro Compounds
  • TRK 820