Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids.
In agreement with the highly lipophilic nature of (-)-delta9-tetrahydrocannabinol, all the endogenous ligands of cannabinoid receptors identified so far are derivatives of long chain fatty acids. N- Arachidonoylethanolamine (anandamide) and some of its polyunsaturated congeners have been found in mammalian brain and shown to activate the CB1 and, with a lower efficacy, CB2 cannabinoid receptor subtypes. More recently, 2-arachidonoylglycerol (2-AG), a widespread intermediate in the metabolism of phosphoglycerides, diacylglycerols and triglycerides, was also found to activate the cannabinoid receptors. The capability of palmitoylethanolamide, an anti-inflammatory metabolite, to activate CB2-like receptors is still being debated. Here we review: 1) the metabolic pathways suggested so far to underlie the biosynthesis and inactivation of anandamide and 2-AG, and 2) the current knowledge of the chemical bases for the interactions of anandamide and 2-AG with proteins of the endogenous cannabinoid system characterized so far, i.e. the CB1 and CB2 receptor subtypes, the membrane anandamide carrier , which facilitates anandamide diffusion into cells, and the enzyme fatty acid amide hydrolase , which catalyzes anandamide and, to a certain extent, 2-AG hydrolysis in vivo.
Di Marzo
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Istituto per la Chimica di Molecole di Interesse Biologico, CNR, 80072 Arco Felice, Napoli, Italy. VDM@TRINC.ICMIB.NA.CNR.IT
Bisogno
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De Petrocellis
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L
Melck
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D
Martin
B R
BR
D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000138:chemical synthesis / Q000494:pharmacology*; D013759:Dronabinol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D063388:Endocannabinoids; D005227:Fatty Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D006213:Hallucinogens / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D053284:Polyunsaturated Alkamides
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005227:Fatty Acids; D006213:Hallucinogens; D053284:Polyunsaturated Alkamides; D013759:Dronabinol; C078814:anandamide