Gul Halise Inci, Calls Unsal, Ozturk Zeynep, Tutar Emre, Calikiran Leyla
Ataturk University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Erzurum, Turkey.
Arzneimittelforschung. 2007;57(3):133-6. doi: 10.1055/s-0031-1296595.
Bis-Mannich bases, bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 1-4, and their corresponding structural and non-classical isomers, 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinol hydrochlorides 5-8, were synthesized. The aryl part was phenyl in 1 and 5, p-methylphenyl in 2 and 6, p-chlorophenyl in 3 and 7, and 2-thienyl in 4 and 8. The chemical stuructures of the compounds were confirmed by 1H-NMR, 13C-NMR, UV, IR and elemental analyses. Anticonvulsant activities of the compounds were evaluated by the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scMet) tests in the dose range of 30-300 mg/kg. Alterations in biological activity depending on modifications in chemical structure were also followed. Compounds 1-4, 6, and 8 were toxic and caused death of the animals 20 min after the injection. Compounds 2, 3 and 6 were also neurotoxic at the 100 mg/kg dose level. While only compound 7 was active in the scMet test at 300 mg/kg within 4 h, all the compounds showed activity in the MES test at different dose levels and time periods. In conclusion, compounds 5 and 7, which were not toxic and did not show neurotoxicity, seemed to be candidate compounds to develop new anticonvulsant compounds useful in the treatment of the grand mal (compounds 5, 7) and petit mal (compound 7) epilepsies.
合成了双曼尼希碱、双（3-芳基-3-氧代丙基）乙胺盐酸盐1-4及其相应的结构异构体和非经典异构体，4-芳基-3-芳基羰基-1-乙基-4-哌啶醇盐酸盐5-8。在化合物1和5中芳基部分为苯基，在2和6中为对甲基苯基，在3和7中为对氯苯基，在4和8中为2-噻吩基。通过1H-NMR、13C-NMR、紫外、红外光谱及元素分析确定了化合物的化学结构。在30-300mg/kg剂量范围内，通过最大电休克（MES）和皮下注射戊四氮（scMet）试验评估了这些化合物的抗惊厥活性。还研究了化学结构修饰对生物活性的影响。化合物1-4、6和8有毒，注射后20分钟导致动物死亡。化合物2、3和6在100mg/kg剂量水平时也具有神经毒性。虽然在4小时内只有化合物7在300mg/kg剂量的scMet试验中有活性，但所有化合物在不同剂量水平和时间段的MES试验中均表现出活性。总之，无毒且无神经毒性的化合物5和7似乎是开发用于治疗大发作（化合物5、7）和小发作（化合物7）癫痫的新型抗惊厥化合物的候选化合物。
