取代苄基／萘甲基异喹啉类及有关季铵衍生物的合成与生物活性

SYNTHESIS AND BIOLOGICAL ACTIVITY OF SUBSTITUTED BENZYL/NAPHTHYLMETHYLISOQUINOLINES AND RELATED QUATERNARY AMMONIUM DERIVATIVES

以具心血管活性的异喹啉类生物碱为先导物，结合某些钾通道阻滞剂的结构特征，设计合成了２８个３，４－二氢（Ｉ１～４）和１，２，３，４－四氢苄基／萘甲基异喹啉化合物（ＩＩ１～１８）及有关季铵衍生物（Ｉ５，６和ＩＩ１９～２２）。药理试验表明：除化合物Ｉ４有一定升压作用外，大多化合物有不同程度的降压和减慢心率活性，其中化合物ＩＩ１的降压活性最强。分析定量构效关系发现：化合物母核氮原子电荷愈大（即其绝对值愈小），降压作用愈强；反之，减慢心率作用愈强。异喹啉母核氮原子电荷可能为影响作用于血管或心脏组织的重要因素之一。

In an attempt to search for novel antihypertensive or antiarrhythmic agents,espe-cially compounds mainly acting on calcium or potassium channels,with the isoquinoline alkaloidswhich possessed cardiovascular effects as lead compounds , and on the basis of previous works of ourlaboratory as well as integration of the structural feature of certain potassium channel blockers,28compounds(I1～6and II1～22) were designed and synthesized among which 24 were not reportedpreviously.3,4-Dihydroisoquinolines were first synthesized by the Bischler-Napieralski cyclization with 3,4-disubstituted phenethylamine and aromatic acetic acid as starting materials.N- alkyl substituted tetrahy-droisoquinolines were prepared by the alkylation of tetrahydroisoquinolines with corresponding substitut-ed benzyl halides,or by the reduction of dihydroisoquinoline quaternary ammonium derivatives.Preliminary pharmacological studies invivo showed that most of these com pounds exhibitedvarious degrees of hypotensive and bradycardial effects exceptI4 which exhibited hypertensiveactivity.The hypotensive effect of II 1 was the most potent among these compounds in anaesthetizednormotensive Sprague-Dawley rats.Analysis of theQSAR between hypotensive/bradycardial activities of certain compounds and theirstructural parameters of molecular mechanics(MM 2)showed that the hypotension/ bradycardiaincreased with the increase/decrease of the charge of the n itrogen atom in the isoquinoline nucleus.Thus,the charge of the nitrogen atom might be one of the important factors which could enhance theselectivity of the compounds acting on blood vessels or cardiac tissues.