Discovery of novel CB2 receptor ligands by a pharmacophore-based virtual screening workflow.
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.
Markt
Patrick
P
Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
Feldmann
Clemens
C
Rollinger
Judith Maria
JM
Raduner
Stefan
S
Schuster
Daniela
D
Kirchmair
Johannes
J
Distinto
Simona
S
Spitzer
Gudrun Maria
GM
Wolber
Gerhard
G
Laggner
Christian
C
Altmann
Karl-Heinz
KH
Langer
Thierry
T
Gertsch
Jürg
J
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*
D008024:Ligands; D043885:Receptor, Cannabinoid, CB2