Discovery of novel CB2 receptor ligands by a pharmacophore-based virtual screening workflow

J Med Chem. 2009 Jan 22;52(2):369-78. doi: 10.1021/jm801044g.

Abstract

Cannabinoid receptor 2 (CB(2) receptor) ligands are potential candidates for the therapy of chronic pain, inflammatory disorders, atherosclerosis, and osteoporosis. We describe the development of pharmacophore models for CB(2) receptor ligands, as well as a pharmacophore-based virtual screening workflow, which resulted in 14 hits for experimental follow-up. Seven compounds were identified with K(i) values below 25 microM. The CB(2) receptor-selective pyridine tetrahydrocannabinol analogue 8 (K(i) = 1.78 microM) was identified as a CB(2) partial agonist. Acetamides 12 (K(i) = 1.35 microM) and 18 (K(i) = 2.1 microM) represent new scaffolds for CB(2) receptor-selective antagonists and inverse agonists, respectively. Overall, our pharmacophore-based workflow yielded three novel scaffolds for the chemical development of CB(2) receptor ligands.

Publication types

  • Validation Study

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Database Management Systems
  • Ligands
  • Models, Molecular
  • Radioligand Assay
  • Receptor, Cannabinoid, CB2 / drug effects
  • Receptor, Cannabinoid, CB2 / metabolism*

Substances

  • Ligands
  • Receptor, Cannabinoid, CB2