Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7327-30. doi: 10.1016/j.bmcl.2010.10.061. Epub 2010 Oct 20.

Abstract

Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.

MeSH terms

  • Amides / chemistry*
  • Animals
  • Azabicyclo Compounds / chemical synthesis*
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / pharmacology
  • Bridged Bicyclo Compounds / chemistry*
  • Drug Design
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Mice
  • Microsomes, Liver / metabolism
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Azabicyclo Compounds
  • Bridged Bicyclo Compounds
  • Indoles
  • Piperazines
  • Receptor, Cannabinoid, CB1
  • indole