Benzisothiazoles and β-adrenoceptors:: synthesis and pharmacological investigation of novel propanolamine and oxypropanolamine derivatives in isolated rat tissues
Benzisothiazoles and β-adrenoceptors:: synthesis and pharmacological investigation of novel propanolamine and oxypropanolamine derivatives in isolated rat tissues
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DOI：
10.1007/bf02977894
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发表时间：
2005-12-01
影响因子：
6.7
通讯作者：
Pozzoli, C
中科院分区：
文献类型：
--
作者：
Morini, G;Poli, E;Pozzoli, C
为了检验以苯并异噻唑为基础的药物与β -肾上腺素受体相互作用的能力，合成并测试了一系列1,2-苯并异噻唑衍生物，这些衍生物在2或3位上被各种丙醇胺或氧丙醇胺侧链取代。利用分离的大鼠心房和小肠分别优先表达Q和a-肾上腺素受体介导的反应，研究了这些化合物对β -肾上腺素受体的药理活性。这些产品均未显示出任何β(1)-肾上腺素能受体的激动活性。相反，2-和3-取代的异丙基、丁基、苄基和胡椒基衍生物2a-d和3a-d在心房中引起异丙肾上腺碱诱导的变时作用的可克服的抑制，表明在β(1)-识别位点存在竞争性拮抗作用。pA(2)值显示叔丁基3b和异丙基取代胡椒基衍生物3a最有效。值得注意的是，许多2-取代的丙醇胺活性低于相应的3-取代的氧丙醇胺。除了化合物3b外，这些药物都没有拮抗肠内异丙肾上腺素的肌肉松弛活性，这表明对β(3)-肾上腺素受体没有影响。这些结果证实了苯并噻唑环与β -肾上腺素受体相互作用的能力，并证明了2-丙醇胺取代或3-羟丙醇胺取代产生的化合物对心脏β(1)-肾上腺素受体具有优先拮抗活性。拮抗的程度在很大程度上取决于取代基的性质及其在苯并异噻唑环上的位置。
In an attempt to examine the ability of benzisothiazole-based drugs to interact with beta-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the beta-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the Q,and A-adrenoceptor-mediated responses, respectively. None of these products showed any beta(1)-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tent-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline-induced chronotropic effects in the atria, suggesting competitive antagonism at the beta(1)-recognition site. The pA(2) values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the beta(3)-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the beta-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac beta(1)-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.