Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists

Bioorg Med Chem. 2015 Jan 1;23(1):241-63. doi: 10.1016/j.bmc.2014.11.002. Epub 2014 Nov 8.

Abstract

The cannabinoid receptor 2 (CB2R) has been linked with the regulation of inflammation, and selective receptor activation has been proposed as a target for the treatment of a range of inflammatory diseases such as atherosclerosis and arthritis. In order to identify selective CB2R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, we first performed a ligand-based virtual screen. Subsequent medicinal chemistry optimisation studies led to the identification of a new class of selective CB2R agonists. Several examples showed high levels of activity (EC50<200 nM) and binding affinity (Ki<200 nM) for the CB2R, and no detectable activity at the CB1R. The most promising example, DIAS2, also showed favourable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases.

Keywords: Agonist; Cannabinoid receptor 1; Cannabinoid receptor 2; Inflammation; Ligand-based screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Cannabinoid Receptor Agonists / chemistry
  • Cannabinoid Receptor Agonists / pharmacology*
  • Drug Evaluation, Preclinical / methods
  • Kinetics
  • Ligands
  • Models, Molecular
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Cannabinoid Receptor Agonists
  • Ligands
  • Receptor, Cannabinoid, CB2
  • Small Molecule Libraries