The effect of hydroxylation of linoleoyl amides on their cannabinomimetic properties.
As yet, the physiological significance of hydroxylation of anandamide and linoleoyl amides is unknown. Therefore, we investigated whether hydroxylation of ODNHEtOH and ODNH2 influences their binding abilities to the CB-1 receptor and whether it alters their reactivity towards a fatty acid amide hydrolase (FAAH) from rat brain. Neither the fatty acid amides nor their hydroxylated derivatives were able to displace the potent cannabinoid [3H]CP 55.940 from the CB-1 receptor (Ki > 1 microM). Hydroxylation of ODNHEtOH resulted in a strong reduction of the maximum rate of hydrolysis by a FAAH, but the affinity of FAAH for the substrate remained of the same order of magnitude. Hydroxylation of ODNH2 led to a decrease in the affinity of FAAH for the substrate, but its maximum rate of conversion was unaffected. Furthermore, hydroxylation of ODNHEtOH enhanced its capacity to inhibit competitively the hydrolysis of anandamide. The resulting prolonged lifetime of anandamide and other fatty acid amide derivatives may have a considerable impact on cellular signal transduction.
van der Stelt
M
M
Bijvoet Center for Biomolecular Research, Department of Bio-Organic Chemistry, Utrecht University, The Netherlands.
Paoletti
A M
AM
Maccarrone
M
M
Nieuwenhuizen
W F
WF
Bagetta
G
G
Veldink
G A
GA
Finazzi Agrò
A
A
Vliegenthart
J F
JF
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology; D002186:Cannabinoids / Q000378:metabolism; D003511:Cyclohexanols / Q000378:metabolism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006900:Hydroxylation; D007700:Kinetics; D008041:Linoleic Acids / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D013379:Substrate Specificity; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D002186:Cannabinoids; D003511:Cyclohexanols; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008041:Linoleic Acids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C078814:anandamide