摘要
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.
出处
《药学学报》
CAS
CSCD
北大核心
1994年第2期95-106,共12页
Acta Pharmaceutica Sinica
基金
国家自然科学基金
关键词
异喹啉类
降压药
抗心律失常药
Isoquinolines
Quaternary ammonium
derivatives
Hypotensive agents
Antiarrhythmic agents
QSAR Tmiswork
was supportedbyagrant from the NationalNaturalScience Foundation.
