Efficient Modulation of 纬-Aminobutyric Acid Type A Receptors by Piperine Derivatives

详细信息    查看全文

• 作者：Angela Sch枚ffmann ; Laurin Wimmer ; Daria Goldmann ; Sophia Khom ; Juliane Hintersteiner ; Igor Baburin ; Thomas Schwarz ; Michael Hintersteininger ; Peter Pakfeifer ; Mouhssin Oufir ; Matthias Hamburger ; Thomas Erker ; Gerhard F. Ecker ; Marko D. Mihovilovic ; Steffen Hering
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 10, 2014
• 年：2014
• 卷：57
• 期：13
• 页码：5602-5619
• 全文大小：912K
• ISSN：1520-4804

文摘

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates 纬-aminobutyric acid type A receptors (GABA_AR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABA_AR by means of a two-microelectrode voltage-clamp technique. GABA_AR were expressed in Xenopus laevis oocytes. Structure鈥揳ctivity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABA_AR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABA_A (maximal GABA-induced chloride current modulation (I_GABA-max = 1673% 卤 146%, EC₅₀ = 51.7 卤 9.5 渭M), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC₅₀ = 13.8 卤 1.8 渭M, I_GABA-max = 760% 卤 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABA_AR modulators.