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

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.

• Authors: Matteo Gianella-Borradori, Ivy Christou, Carole J R Bataille, Rebecca L Cross, Graham M Wynne, David R Greaves, Angela J Russell
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 1 Pg. 241-63 (Jan 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 25487422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

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

Topics

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