Department of Pharmacognosy, University of Szeged , H-6720 Szeged, Hungary.
J Nat Prod. 2014 Jul 25;77(7):1663-9. doi: 10.1021/np500292g. Epub 2014 Jun 27.
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'-methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2'-methylbutylamide (4), were identified from Heliopsis helianthoides var. scabra. Compounds 2-4 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 (Ki values of 0.31 and 0.48 μM, respectively). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC50 = 4 μM) and a potent inhibition of anandamide cellular uptake (IC50 = 0.67 μM) 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.
植物源性 N-烷酰胺（NAAs）与哺乳动物内源性大麻素系统（ECS）的相互作用的发现，以及植物内源性 N-酰基乙醇胺信号系统的存在，导致人们重新评估了这组化合物。本文报道了七种 NAAs 的分离及其对 ECS 网络中主要蛋白质靶标的作用评估。从糙叶黄花稔中分离得到了四种 NAA，分别为十八碳-2E、4E、8E、10Z、14Z-戊烯-12-炔酸异丁酰胺（1）、十八碳-2E、4E、8E、10Z、14Z-戊烯-12-炔酸 2'-甲基丁酰胺（2）、十六碳-2E、4E、9Z-三烯-12,14-二炔酸异丁酰胺（3）和十六碳-2E、4E、9,12-四烯酸 2'-甲基丁酰胺（4）。化合物 2-4 为新的天然产物，而 1 则为首次从该种植物中分离得到。先前描述的马卡酰胺，N-（3-甲氧基苄基）-（9Z、12Z、15Z）-十八碳三烯酰胺（5）、N-苄基-（9Z、12Z、15Z）-十八碳三烯酰胺（6）和 N-苄基-（9Z、12Z）-十八碳二烯酰胺（7），则从秘鲁玛咖中分离得到。N-甲基丁酰胺 4 和 N-苄基酰胺 7 对大麻素 CB1 受体具有亚微摩尔和选择性的结合亲和力（Ki 值分别为 0.31 和 0.48 μM）。值得注意的是，化合物 7 还表现出较弱的脂肪酸酰胺水解酶（FAAH）抑制作用（IC50=4 μM）和较强的花生四烯酸细胞摄取抑制作用（IC50=0.67 μM），其抑制作用强于对照物 OMDM-2 和 UCM707。化合物 7 对 ECS 的多药理学作用突出表明，拟 arachidonoyl 的 9Z、12Z 双键系统在 linoleoyl 基团中对 NAA 的整体大麻样作用的潜在参与。这项研究为植物源性 NAAs 的内源性大麻素底物模拟提供了更多有力证据，并揭示了秘鲁玛咖根的直接和间接大麻样作用。
