TY - JOUR
T1 - New resorcinol-anandamide "hybrids" as potent cannabinoid receptor ligands endowed with antinociceptive activity in vivo
AU - Brizzi, Antonella
AU - Brizzi, Vittorio
AU - Cascio, Maria Grazia
AU - Corelli, Federico
AU - Guida, Francesca
AU - Ligresti, Alessia
AU - Maione, Sabatino
AU - Martinelli, Adriano
AU - Pasquini, Serena
AU - Tuccinardi, Tiziano
AU - Di Marzo, Vincenzo
N1 - Acknowledgement: The authors from the University of Siena thank the Ministero dell’Università e della Ricerca (PRIN 2006, Prot. n 2006030948_002) for financial support. Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH Grant P41 RR-01081). The authors are grateful to Marco Allarà for technical assistance with the binding assays.
PY - 2009/4/23
Y1 - 2009/4/23
N2 - Bearing in mind the pharmacophoric requirements of both (-)-trans-Δ 9-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB 1 and CB 2 ligand, with K i values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB 2 receptor (K i(CB 1)) 1 μM, K i(CB 2)) 35 nM).
AB - Bearing in mind the pharmacophoric requirements of both (-)-trans-Δ 9-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB 1 and CB 2 ligand, with K i values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB 2 receptor (K i(CB 1)) 1 μM, K i(CB 2)) 35 nM).
UR - http://www.scopus.com/inward/record.url?scp=65249188375&partnerID=8YFLogxK
U2 - 10.1021/jm8016255
DO - 10.1021/jm8016255
M3 - Article
C2 - 19331413
AN - SCOPUS:65249188375
VL - 52
SP - 2506
EP - 2514
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -