Abstract

Histamine H₃ receptors (H₃R) antagonists/inverse agonists are becoming a promising therapeutic approach for epilepsy. In this article, novel nonimidazole H₃R antagonists/inverse agonists have been designed and synthesised via hybriding the H₃R pharmacophore (aliphatic amine with propyloxy chain) with the 1,2,4-triazole moiety as anticonvulsant drugs. The majority of antagonists/inverse agonists prepared here exerted moderate to robust activities in cAMP-response element (CRE) luciferase screening assay. 1-(3-(4-(3-Phenyl-4H-1,2,4-triazol-4-yl)phenoxy)propyl)piperidine (3l) and 1-(3-(4-(3-(4-chlorophenyl)-4H-1,2,4-triazol-4-yl)phenoxy)propyl)piperidine (3m) displayed the highest H₃R antagonistic activities, with IC₅₀ values of 7.81 and 5.92 nM, respectively. Meanwhile, the compounds with higher H₃R antagonistic activities exhibited protection for mice in maximal electroshock seizure (MES)-induced convulsant model. Moreover, the protection of 3m against the MES induced seizures was fully abrogated when mice were co-treated with RAMH, a CNS-penetrant H₃R agonist, which suggested that the potential therapeutic effect of 3m was through H₃R. These results indicate that the attempt to find new anticonvulsant among H₃R antagonists/inverse agonists is practicable.

摘要

组胺H ₃受体（H ₃ R）拮抗剂/反向激动剂正成为癫痫的一种有前途的治疗方法。在本文中，通过将H ₃ R药效团（带有丙氧基链的脂族胺）与1,2,4-三唑部分作为抗惊厥药混合，设计并合成了新型的非咪唑H ₃ R拮抗剂/反向激动剂。此处制备的大多数拮抗剂/反向激动剂在cAMP反应元件（CRE）荧光素酶筛选试验中发挥中等至强效的作用。1-（3-（4-（3-苯基-4 H -1,2,4-三唑-4-基）苯氧基）丙基）哌啶（3l）和1-（3-（4-（3-（4 -氯苯基）-4 H-1,2,4-三唑-4（基）苯氧基）丙基）哌啶（3m）表现出最高的H ₃ R拮抗活性，IC ₅₀值分别为7.81和5.92 nM。同时，具有较高H ₃ R拮抗活性的化合物在最大电击惊厥（MES）诱导的惊厥模型中对小鼠具有保护作用。此外，保护3米靠在MES诱导的癫痫发作完全被废止时小鼠用RAMH，一个CNS渗透剂ħ共同处理₃ R激动剂，提示的潜在治疗效果3米是至H ₃ R.这些结果表明在H _3中寻找新的抗惊厥药的尝试R拮抗剂/反向激动剂是可行的。