Discovery of Novel CB2 Receptor Ligands by a Pharmacophore-Based Virtual Screening Workflow

Cannabinoid receptor 2 (CB2 receptor) ligands are potential candidates for the therapy of chronic pain, inflammatory disorders, atherosclerosis, and osteoporosis. We describe the development of pharmacophore models for CB2 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 mu M. The CB2 receptor-selective pyridine tetrahydrocannabinol analogue 8 (K-i = 1.78 mu M) was identified as a CB2 partial agonist. Acetamides 12 (K-i = 1.35 mu M) and 18 (K-i = 2.1 mu M) represent new scaffolds for CB2 receptor-selective antagonists and inverse agonists, respectively. Overall, our pharmacophore-based workflow yielded three novel scaffolds for the chemical development of CB2 receptor ligands.