title: Resorcinol-sn-glycerol derivatives: novel 2-arachidonoylglycerol mimetics endowed with high affinity and selectivity for cannabinoid type 1 receptor.
abstract: 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 CB1 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 CB1 (Ki in the nanomolar range) than for CB2 receptors plus the potential to be exploited as useful hits for the development of novel 2-AG mimetics.
authors: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy. brizzi3@unisi.it
authors: Antonella
authors: A
authors: Brizzi
authors: Maria Grazia
authors: MG
authors: Cascio
authors: Maria
authors: M
authors: Frosini
authors: Alessia
authors: A
authors: Ligresti
authors: Francesca
authors: F
authors: Aiello
authors: Irene
authors: I
authors: Biotti
authors: Vittorio
authors: V
authors: Brizzi
authors: Roger Guy
authors: RG
authors: Pertwee
authors: Federico
authors: F
authors: Corelli
authors: Vincenzo
authors: V
authors: Di Marzo
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D063388:Endocannabinoids; D004950:Esterases / Q000097:blood; D004952:Esters; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005989:Glycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018716:Molecular Mimicry; D050178:Monoglycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D012118:Resorcinols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C570531:1,3-dihydroxypropan-2-yl 11-(2-hexyl-5-hydroxyphenoxy)undecanoate; C570532:1,3-dihydroxypropan-2-yl 11-(3-hydroxy-5-(2-methyloctan-2-yl)phenoxy)undecanoate; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004952:Esters; D004987:Ethers; D005989:Glycerides; D050178:Monoglycerides; D010636:Phenols; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D012118:Resorcinols; C094503:glyceryl 2-arachidonate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004950:Esterases