Rational design and synthesis of an orally active indolopyridone as a novel conformationally constrained cannabinoid ligand possessing antiinflammatory properties

J Med Chem. 2003 May 22;46(11):2110-6. doi: 10.1021/jm020329q.

Abstract

A series of unique indazoles and pyridoindolones have been rationally designed and synthesized as novel classes of cannabinoid ligands based on a proposed bioactive amide conformation. This has led to the discovery of the novel indolopyridone 3a as a conformationally constrained cannabinoid ligand that displays high affinity for the CB2 receptor (K(i)(CB2) = 1.0 nM) and possesses antiinflammatory properties when administered orally in an in vivo murine inflammation model.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cannabinoids / metabolism*
  • Cells, Cultured
  • Cricetinae
  • Drug Design
  • Female
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Ligands
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Conformation
  • Norbornanes / chemical synthesis*
  • Norbornanes / chemistry
  • Norbornanes / pharmacology
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry
  • Pyridones / pharmacology
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists*
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 2,5-dihydro-6-methoxy-5-(2-(4-morpholinyl)ethyl)-2-(1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-1H-pyrido(4,3-b)indol-1-one
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cannabinoids
  • Indoles
  • Ligands
  • Lipopolysaccharides
  • Norbornanes
  • Pyridones
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Tumor Necrosis Factor-alpha