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为寻找主要作用于钙或钾通道的新型降压或抗心律失常药,在已有研究基础上,结合一些钙拮抗剂和钾通道调控剂的结构特征,设计合成了26个N-胺乙酰基取代的苄基/萘甲基四氢异喹啉化合物(Ⅳ_(1～26))。[~3H]-尼群地平结合试验表明:活性较好的化合物Ⅳ_8和Ⅳ_(17)等通过作用于L-型钙通道二氢吡啶(DHP)受体而产生心血管作用。化合物Ⅳ_8和Ⅳ_(17)的钙拮抗活性和对正常及高血压大鼠的降压作用均强于粉防己碱,且在降压同时还具减慢心率作用。部分化合物的定量构效关系研究发现:DHP受体亲和力与分子范德华体积及母核氮原子电荷正相关,而与分子非正则能及分子疏水性负相关;结果还提示:化合物与DHP受体的结合方式可能是形成“电荷转移复合物”。
In order to find novel antihypertensive or antiarrhythmic drugs that mainly act on calcium or potassium channels, based on previous studies and combined with structural features of some calcium antagonists and potassium channel modulators, 26 N-amine acetyl groups Substituted benzyl / naphthylmethyltetrahydroisoquinoline compounds (IV_ (1-26)). The combination of [~ 3H] -nitrendipine showed that the more active compounds Ⅳ_8 and Ⅳ_ (17) and so on had a cardiovascular effect by acting on the L-type calcium channel dihydropyridine (DHP) receptor. Compounds Ⅳ_8 and Ⅳ_ (17) calcium antagonistic activity and antihypertensive effect on normal and hypertensive rats were stronger than tetrandrine, and at the same time with a heart rate lowering effect. Quantitative structure-activity relationship study of some compounds showed that DHP receptor affinity was positively correlated with molecular van der Waals volume and nuclear charge, but negatively correlated with molecular non-regularity and molecular hydrophobicity. The results also suggested that the binding of DHP receptor to DHP receptor The bond may form a “charge-transfer complex.”