摘要
粉防己碱有钙拮抗作用,临床试用于治疗高血压,其裂解产物钙拮抗作用降低,但有α-肾上腺素能受体拮抗作用,本文以裂解物为先导化合物设计合成了两类取代的四氢异喹啉衍生物Ⅲ及Ⅳ。初步药理试验表明:大部分化合物有α-肾上腺素能受体拮抗作用,少数化合物钙拮抗活性有所增强,其中Ⅲ_(15,19)对正常麻醉大鼠有一定的降压作用、Ⅳ_(17,19)对实验性动物心律失常有明显的保护作用。部分化合物量化计算表明:化合物与α_1-受体作用方式可能是形成电荷转移复合物。
Tetrandrine possesses calcium antagonistic and hypotensive effects. It was cleaved into two compounds O-methylcoclaurine (Ⅰ) and N-methylarmepavine (Ⅱ) by Na/NH_3. Pharmacological test indicated that Ⅰ and Ⅱ showed weaker calcium antagonistic activity but having α-adrenoceptor antagonistic effect.With Ⅰ and Ⅱ as lead compounds as well as integration of some structural feature of calcium antagonists and SAR of antiarrhythmic drugs, two kindsof substituted tetrahydroisoquinoline derivatives Ⅲ, Ⅳ were designed and synthesized in order to search for novel cardiovascular drugs.Tetrahydroisoquinoline compounds were first synthesized by the Bischler-Napiraski cyclization with substituted phenethylamine and aromatic acetic acid or substituted cinnamic acid as starting materials. N-alkylsubstituted tetrahydroisoquinoline compounds were prepared by the reaction of 4 with alkyl halide to produce 5, then reduction of 5 by KBH_4 to give Ⅲ_(13～25). The synthesis of N-alkylaminoethyl substituted tetrahyroisoquinoline compounds involved the reaction of 6 with chloroacetyl chloride to obtain Ⅳ_(1～3), the reaction of Ⅳ_(1～3) with secondary amineto produce 9, and then reduction of 9 with LiAlH_4 to give Ⅳ_(16-19).Preliminary tests showed that most of these compounds exhibited varied degree of α-adrenoceptor antagonistic effect, and some of them possess calcium antagonistic activity. In anesthetic normal rats Ⅲ_(15,19) showed certain degree of hypotensive effect. Ⅳ_(10,11) exhibited significant protective effect on experimental arrhythmic animals. The results of quantum chemical calculation of some compounds demonstrate that the compounds might act with α_1-adrenoceptor by forming charge-transfer complex.
出处
《药学学报》
CAS
CSCD
北大核心
1990年第11期815-823,共9页
Acta Pharmaceutica Sinica
基金
国家医药局新药研究基金
关键词
四氢异喹啉
钙抗剂作用
Tetrahydroisoquinoline
α-Adrenoceptor antagonistic effect
Calcium antagonistic activity
Antiarrhythmic drugs
