The effect of hydroxylation of linoleoyl amides on their cannabinomimetic properties

• Published in: FEBS letters 1997-10, Vol.415 (3), p.313-316
• Main Authors: van der Stelt, Marcelis, Paoletti, Anna Maria, Maccarrone, Mauro, Nieuwenhuizen, Willem F, Bagetta, Giacinto, Veldink, Gerrit A, Finazzi Agrò, Alessandro, Vliegenthart, Johannes F.G
• Format: Article
• Language: English
• Subjects: 12/15-HETE; 12/15-hydroxyeicosatetraenoic acid; 13-(S)-hydroxy-9Z,11E-octadeca-9,11-dienoyl amide; 13-(S)-hydroxy-9Z,11E-octadeca-9,11-dienoyl ethanolamide; 13-HODNH2; 13-HODNHEtOH; 9Z,12Z-octadeca-9,12-dienoyl amide; 9Z,12Z-octadeca-9,12-dienoyl ethanolamide; Amidohydrolases - antagonists & inhibitors; Amidohydrolases - metabolism; Anandamide; Animals; Arachidonic Acids - metabolism; Binding, Competitive; bovine serum albumin; Brain - enzymology; BSA; cannabinoid binding receptor-1/2; Cannabinoid receptor; Cannabinoids - metabolism; CB-1/2; Cyclohexanols - metabolism; Endocannabinoids; Enzyme Inhibitors - pharmacology; FAAH; Fatty acid amide hydrolase; Hydroxylation; Kinetics; LCS; Linoleic Acids - metabolism; Linoleic Acids - pharmacology; Lipoxygenase; liquid scintillation cocktail; Male; ODNH2; ODNHEtOH; PEI; phenylmethylsulfonyl fluoride; PMSF; polyethylene imine; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug - metabolism; reversed phase high performance liquid chromatography; RP-HPLC; Substrate Specificity; thin layer chromatography; TLC
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(97)01148-4

As yet, the physiological significance of hydroxylation of anandamide and linoleoyl amides is unknown. Therefore, we investigated whether hydroxylation of ODNHEtOH and ODNH 2 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 ( K i>1 μM). 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 ODNH 2 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.