Pharmacological properties of TRK-820 on cloned mu-, delta- and kappa-opioid receptors and nociceptin receptor

Eur J Pharmacol. 1999 Jul 2;376(1-2):159-67. doi: 10.1016/s0014-2999(99)00369-6.


We analyzed the pharmacological properties of 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6b eta-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (TRK-820) using Chinese hamster ovary (CHO) cells expressing cloned rat mu-, delta- and kappa-opioid receptors and human nociceptin receptor. TRK-820 showed high affinity for the kappa-opioid receptor, with a Ki value of 3.5 +/- 0.9 nM. In CHO cells expressing kappa-opioid receptors, TRK-820 inhibited forskolin-stimulated cAMP accumulation, and the maximal inhibitory effect was equivalent to that of (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiny l)-1-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593), a full agonist of kappa-opioid receptor. In CHO cells expressing mu-opioid receptors, TRK-820 inhibited cAMP accumulation, but the maximal inhibitory effect was significantly smaller than that of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO), a full agonist of mu-opioid receptor. In CHO cells expressing delta-opioid receptor, the inhibitory effect of TRK-820 on cAMP accumulation was very weak. Using site-directed mutagenesis, the high affinity of TRK-820 for the kappa-opioid receptor was revealed to require Glu297. TRK-820 bound to the nociceptin receptor with a Ki value of 380 +/- 50 nM. TRK-820 by itself had no effect on cAMP accumulation in CHO cells expressing nociceptin receptors, but significantly antagonized the nociceptin (10 nM)-mediated inhibition of cAMP accumulation at high concentrations. These results indicate that TRK-820 acts as a full agonist for the kappa-opioid receptor, a partial agonist for the mu-opioid receptor and a low-affinity antagonist for the nociceptin receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cloning, Molecular
  • Cricetinae
  • Humans
  • Ligands
  • Morphinans / metabolism
  • Morphinans / pharmacology*
  • Mutation
  • Naloxone / analogs & derivatives
  • Naloxone / metabolism
  • Naloxone / pharmacology
  • Narcotic Antagonists / metabolism
  • Radioligand Assay
  • Rats
  • Receptors, Opioid / agonists
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid / metabolism
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / drug effects*
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / drug effects*
  • Receptors, Opioid, kappa / genetics
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / drug effects*
  • Receptors, Opioid, mu / metabolism
  • Spiro Compounds / metabolism
  • Spiro Compounds / pharmacology*


  • Ligands
  • Morphinans
  • Narcotic Antagonists
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Spiro Compounds
  • naloxone benzoylhydrazone
  • TRK 820
  • Naloxone
  • nociceptin receptor