Synthesis of new opioid derivatives with a propellane skeleton and their pharmacologies: part 3, novel propellane derivatives with pentacyclic skeletons

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7697-701. doi: 10.1016/j.bmcl.2012.09.102. Epub 2012 Oct 5.

Abstract

Previously reported propellane derivative KNT-42 preferred the κ receptor and functioned as a message part in the message-address concept, but its affinity for the κ receptor was not high. To improve affinity, we synthesized five pentacyclic propellane derivatives designed for the purpose of fixing the conformation of KNT-42. The etheno- and ethano-bridged derivatives SYK-347 and SYK-393 exhibited high affinity and selectivity for the κ receptor, whereas the other derivatives did not. These results would be due to the different ranges of movement of the basic nitrogens and less basicity of the nitrogens due to the electron withdrawing effect of the introduced hydroxy or keto group. SYK-347 and SYK-393 preferring the κ receptor were expected to be useful for designing selective ligands for opioid receptor types, especially the κ receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / chemical synthesis
  • Analgesics, Opioid / chemistry
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Bridged-Ring Compounds / chemical synthesis
  • Bridged-Ring Compounds / chemistry
  • Bridged-Ring Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Mice
  • Molecular Conformation
  • Receptors, Opioid, kappa / agonists*
  • Structure-Activity Relationship

Substances

  • Analgesics, Opioid
  • Bridged-Ring Compounds
  • Receptors, Opioid, kappa