Design and synthesis of novel opioid ligands with an azabicyclo[2.2.2]octane skeleton having a 7-amide side chain and their pharmacologies

Bioorg Med Chem. 2013 Jun 1;21(11):3032-50. doi: 10.1016/j.bmc.2013.03.026. Epub 2013 Apr 3.

Abstract

Several derivatives with an azabicyclo[2.2.2]octane skeleton having a 7-amide side chain were synthesized. Compounds that had an electron-donating group exhibited high affinity for the μ opioid receptor while those with a bulky substituent at the 8-nitrogen atom had low affinities for all receptor types. High affinities and selectivities for the κ receptor resulted from the introduction of the longer amide side chain at the 7α-position. Our studies indicate that the orientation of the amide side chain at the 7-position within the azabicyclo[2.2.2]octane skeleton is related to selectivity for the κ receptor.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Analgesics, Opioid / chemical synthesis*
  • Analgesics, Opioid / chemistry
  • Azabicyclo Compounds / chemical synthesis*
  • Azabicyclo Compounds / chemistry
  • Biological Assay
  • Drug Design
  • Humans
  • Ligands
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / chemistry*
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / chemistry*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / chemistry*
  • Sensitivity and Specificity
  • Structure-Activity Relationship

Substances

  • Amides
  • Analgesics, Opioid
  • Azabicyclo Compounds
  • Ligands
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu