TY - JOUR
T1 - Design, synthesis, and binding studies of new potent ligands of cannabinoid receptors
AU - Brizzi, Antonella
AU - Brizzi, Vittorio
AU - Cascio, Maria Grazia
AU - Bisogno, Tiziana
AU - Sirianni, Rossella
AU - Marzo, Vincenzo Di
N1 - Acknowledgement: We thank the Università degli Studi di Siena, Italy, for financial support. Dr. Alessia Ligresti and Mr. Paolo Cavallo for technical assistance with the assays. Dr. Luisa Chiasserini for NOESY spectra.
PY - 2005/11/1
Y1 - 2005/11/1
N2 - Despite their different chemical structures, Δ9- tetrahydrocannabinol (THC) and anandamide (AEA) have common pharmacological properties. This study was aimed at finding new cannabinoid receptor ligands that overcome the instability of AEA and its analogues. To this end we planned the synthesis of a series of compounds which retained both a rigid structure, like that of plant cannabinoids, and a flexible portion similar to that of anandamide. Binding studies on CB1 and CB2 receptors, anandamide membrane transporter (AMT), and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds have high affinity and specificity for cannabinoid CB1 and CB2 receptors. Compound 25 is a potent CB1 and CB2 ligand, with affinity constants significantly lower than AEA and similar to WIN 55-212, compound 52 is a potent CB2 ligand, although not very selective over CB1 receptors, and compound 43 is CB2 ligand, with at least a 26-fold selectivity over CB1 receptors. Compound 25 behaved as a inverse agonist at CB1 receptors as assessed in the cyclic AMP functional assay.
AB - Despite their different chemical structures, Δ9- tetrahydrocannabinol (THC) and anandamide (AEA) have common pharmacological properties. This study was aimed at finding new cannabinoid receptor ligands that overcome the instability of AEA and its analogues. To this end we planned the synthesis of a series of compounds which retained both a rigid structure, like that of plant cannabinoids, and a flexible portion similar to that of anandamide. Binding studies on CB1 and CB2 receptors, anandamide membrane transporter (AMT), and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds have high affinity and specificity for cannabinoid CB1 and CB2 receptors. Compound 25 is a potent CB1 and CB2 ligand, with affinity constants significantly lower than AEA and similar to WIN 55-212, compound 52 is a potent CB2 ligand, although not very selective over CB1 receptors, and compound 43 is CB2 ligand, with at least a 26-fold selectivity over CB1 receptors. Compound 25 behaved as a inverse agonist at CB1 receptors as assessed in the cyclic AMP functional assay.
UR - http://www.scopus.com/inward/record.url?scp=28544438920&partnerID=8YFLogxK
U2 - 10.1021/jm0501533
DO - 10.1021/jm0501533
M3 - Article
C2 - 16279794
AN - SCOPUS:28544438920
VL - 48
SP - 7343
EP - 7350
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -