title: Discovery of novel CB2 receptor ligands by a pharmacophore-based virtual screening workflow.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Clemens
authors.initials: C
authors.lastname: Feldmann
authors.forename: Judith Maria
authors.initials: JM
authors.lastname: Rollinger
authors.forename: Stefan
authors.initials: S
authors.lastname: Raduner
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.forename: Gudrun Maria
authors.initials: GM
authors.lastname: Spitzer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003628:Database Management Systems; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D008024:Ligands; D043885:Receptor, Cannabinoid, CB2