CONFORMATIONALLY RESTRAINED ANALOGS OF SYMPATHOMIMETIC CATECHOLAMINES - SYNTHESIS, CONFORMATIONAL-ANALYSIS, AND ADRENERGIC ACTIVITY OF ISOCHROMAN DERIVATIVES
CONFORMATIONALLY RESTRAINED ANALOGS OF SYMPATHOMIMETIC CATECHOLAMINES - SYNTHESIS, CONFORMATIONAL-ANALYSIS, AND ADRENERGIC ACTIVITY OF ISOCHROMAN DERIVATIVES
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DOI：
10.1021/jm00073a006
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发表时间：
1993-10-15
影响因子：
7.3
通讯作者：
BARRETTA, GU
中科院分区：
文献类型：
--
作者：
MACCHIA, B;BALSAMO, A;BARRETTA, GU
在以前的论文处理的构象和生物药理学活性的构象限制类似物的拟交感神经的儿茶酚胺（NE和ISO）的研究，建议提出了三维分子模型A，B和C，这些模型提供了有关的立体要求α 1，α 2，β 1和β 2肾上腺素受体的直接激活，分别。1-（氨甲基）-6，7-二羟基异色满11和12以及1-（氨甲基）-5，6-二羟基异色满13和14（1-AMDIC）是NE和ISO的两种不同类型的半刚性类似物。通过放射性配体结合试验和分离制剂的功能试验，对1-AMDIC 11-14的α 1、α 2、β 1和β 2肾上腺素能特性进行了体外评价，并与其母体化合物（NE和ISO）进行了比较。通过H-1 NMR光谱和理论计算进行的构象研究的结果表明，在这些1-AMDIC中，假定的活性基团（芳基部分，胺氮和苄基醚氧）的空间关系对应于NE和ISO在其优选构象中发现的空间关系，这也被证明是模型A-C中的药效构象。通过比较I-AMDIC 11-14的立体结构与它们的生物药理学性质，可以获得关于α 2肾上腺素受体活化的模型B的进一步定义; 1-AMDIC 11和12与分子模型C的叠加使得可以检测β-AMDIC的区域。肾上腺素能受体，其可能阻碍肾上腺素能药物与这些受体的匹配，所述肾上腺素能药物是儿茶酚胺的类似物。
In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha1, alpha2, beta1, and beta2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha1, alpha2, beta1, and beta2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both H-1 NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the I-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it.possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.