Identification of Endocannabinoid System-Modulating N-Alkylamides from Heliopsis helianthoides var. scabra and Lepidium meyenii

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• 作者：Zsanett Hajdu ; Simon Nicolussi ; Mark Rau ; L谩szl贸 Lor谩ntfy ; Peter Forgo ; Judit Hohmann ; Dezs艖 Csupor ; J眉rg Gertsch
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：July 25, 2014
• 年：2014
• 卷：77
• 期：7
• 页码：1663-1669
• 全文大小：318K
• ISSN：1520-6025

文摘

The discovery of the interaction of plant-derived N-alkylamides (NAAs) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous N-acylethanolamine signaling system have led to the re-evaluation of this group of compounds. Herein, the isolation of seven NAAs and the assessment of their effects on major protein targets in the ECS network are reported. Four NAAs, octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid isobutylamide (1), octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid 2鈥?methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2鈥?methylbutylamide (4), were identified from Heliopsis helianthoides var. scabra. Compounds 2鈥? are new natural products, while 1 was isolated for the first time from this species. The previously described macamides, N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (5), N-benzyl-(9Z,12Z,15Z)-octadecatrienamide (6), and N-benzyl-(9Z,12Z)-octadecadienamide (7), were isolated from Lepidium meyenii (Maca). N-Methylbutylamide 4 and N-benzylamide 7 showed submicromolar and selective binding affinities for the cannabinoid CB₁ receptor (K_i values of 0.31 and 0.48 渭M, respectively). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC₅₀ = 4 渭M) and a potent inhibition of anandamide cellular uptake (IC₅₀ = 0.67 渭M) that was stronger than the inhibition obtained with the controls OMDM-2 and UCM707. The pronounced ECS polypharmacology of compound 7 highlights the potential involvement of the arachidonoyl-mimicking 9Z,12Z double-bond system in the linoleoyl group for the overall cannabimimetic action of NAAs. This study provides additional strong evidence of the endocannabinoid substrate mimicking of plant-derived NAAs and uncovers a direct and indirect cannabimimetic action of the Peruvian Maca root.