TY - JOUR
T1 - Resorcinol-sn-glycerol derivatives
T2 - Novel 2-Arachidonoylglycerol mimetics endowed with high affinity and selectivity for cannabinoid type 1 receptor
AU - Brizzi, Antonella
AU - Cascio, Maria Grazia
AU - Frosini, Maria
AU - Ligresti, Alessia
AU - Aiello, Francesca
AU - Biotti, Irene
AU - Brizzi, Vittorio
AU - Pertwee, Roger Guy
AU - Corelli, Federico
AU - Di Marzo, Vincenzo
N1 - Acknowledgement: Authors from the University of Siena wish to thank the Ministero dell’Università e della Ricerca (PRIN 2006, Prot. no. 2006030948_002) for financial support. We are grateful to Marco Allarà for technical assistance with the binding assays. Thanks are also due to Dr. Stefania Lamponi for her skillful support in the human plasma sample preparation.
PY - 2011/12/22
Y1 - 2011/12/22
N2 - Since the discovery of the endocannabinoid system, evidence has been progressively accumulating to suggest that 2-arachidonoylglycerol (2-AG) rather than anandamide (AEA) is the endogenous ligand for both cannabinoid (CB) receptors. Moreover, other studies have shown that another lipid molecule, 2-arachidonyl-glycerol ether (2-AGE, noladin ether), which acts as a full agonist at cannabinoid receptors, might occur in tissues. Having previously designed a resorcinol-AEA hybrid model, in this paper we have explored the cannabinoid receptor binding properties, the CB 1 functional activity, and the stability to plasma esterases of a novel series of compounds characterized by the conversion of the amide head into the glycerol-ester or glycerol-ether head, typical of 2-AG or the "putative" endocannabinoid 2-AGE, respectively. Glyceryl esters 39 and 41 displayed greater potency for CB 1 (K i in the nanomolar range) than for CB 2 receptors plus the potential to be exploited as useful hits for the development of novel 2-AG mimetics. (Figure presented)
AB - Since the discovery of the endocannabinoid system, evidence has been progressively accumulating to suggest that 2-arachidonoylglycerol (2-AG) rather than anandamide (AEA) is the endogenous ligand for both cannabinoid (CB) receptors. Moreover, other studies have shown that another lipid molecule, 2-arachidonyl-glycerol ether (2-AGE, noladin ether), which acts as a full agonist at cannabinoid receptors, might occur in tissues. Having previously designed a resorcinol-AEA hybrid model, in this paper we have explored the cannabinoid receptor binding properties, the CB 1 functional activity, and the stability to plasma esterases of a novel series of compounds characterized by the conversion of the amide head into the glycerol-ester or glycerol-ether head, typical of 2-AG or the "putative" endocannabinoid 2-AGE, respectively. Glyceryl esters 39 and 41 displayed greater potency for CB 1 (K i in the nanomolar range) than for CB 2 receptors plus the potential to be exploited as useful hits for the development of novel 2-AG mimetics. (Figure presented)
UR - http://www.scopus.com/inward/record.url?scp=84055221870&partnerID=8YFLogxK
U2 - 10.1021/jm200529h
DO - 10.1021/jm200529h
M3 - Article
C2 - 22044209
AN - SCOPUS:84055221870
SN - 0022-2623
VL - 54
SP - 8278
EP - 8288
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -