Synthesis of all-trans anandamide: a substrate for fatty acid amide hydrolase with dual effects on rabbit platelet activation.
Anandamide (AEA) presents the four double bonds in the cis configuration, deriving from the arachidonic acid moiety. In the context of an antisense strategy based on the double bond configuration, all-trans AEA (t-AEA) was synthesized in high yield starting from all-trans methyl arachidonate and ethanolamine in the presence of KCN. t-AEA was assayed on rabbit platelet aggregation, obtaining effect only at high concentrations (>10(-4) M) after an also concentration-dependent lag phase. At lower concentrations it inhibited PAF-induced rabbit platelet aggregation with an IC(50)=4.6 x 10(-6) M. In contrast to anandamide, the activation of platelets was not due to the conversion of t-AEA to trans arachidonic acid, as ascertained by negative results with FAAH inhibitors. However, t-AEA was found to be a substrate for fatty acid amide hydrolase (FAAH), the enzyme that cleaves anandamide and regulates in vivo the magnitude and duration of the signaling induced by this lipid messenger.
Ferreri
Carla
C
ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy. cferreri@isof.cnr.it
Anagnostopoulos
Dimitris
D
Lykakis
Ioannis N
IN
Chatgilialoglu
Chryssostomos
C
Siafaka-Kapadai
Athanassia
A
D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000138:chemical synthesis / Q000494:pharmacology*; D063388:Endocannabinoids; D019856:Ethanolamine / Q000378:metabolism; D050356:Lipid Metabolism; D015539:Platelet Activation / Q000187:drug effects*; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D019856:Ethanolamine; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide