Department of Pharmacology and Toxicology and §Division of Drug Design and Medicinal Chemistry, Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, A-1090 Vienna, Austria.
J Med Chem. 2014 Jul 10;57(13):5602-19. doi: 10.1021/jm5002277. Epub 2014 Jun 27.
Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure-activity 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 GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABAAR modulators.
胡椒碱激活 TRPV1（瞬时受体电位香草酸类型 1 受体）受体并调节 GABAAR（γ-氨基丁酸 A 型受体）。我们合成了 76 种胡椒碱类似物文库，并通过双微电极电压钳技术分析了它们对 GABAAR 的影响。GABAAR 在非洲爪蟾卵母细胞中表达。建立了构效关系（SAR）以确定对效率和效力至关重要的结构要素。胡椒碱衍生物的效率通过用 N,N-二丙基、N,N-二异丙基、N,N-二丁基、对甲基哌啶或 N,N-双（三氟乙基）基团替代哌啶基显著提高。通过用 N,N-二丁基、N,N-二异丁基或 N,N-双三氟乙基基团替代哌啶基来增强效力。连接体修饰并未显著增强对 GABAAR 的影响。化合物 23[（2E,4E）-5-（1,3-苯并二恶唑-5-基）-N,N-二丙基-2,4-戊二酰胺]诱导最强的 GABAA 调制（最大 GABA 诱导的氯离子电流调制（IGABA-max=1673%±146%，EC50=51.7±9.5μM），而 25[（2E,4E）-5-（1,3-苯并二恶唑-5-基）-N,N-二丁基-2,4-戊二酰胺]显示出最高的效力（EC50=13.8±1.8μM，IGABA-max=760%±47%）。化合物 23 在小鼠中引起的焦虑缓解作用明显强于胡椒碱，因此可能成为开发新型 GABAAR 调节剂的起点。
