Synthesis and evaluation of trimetoquinol derivatives: novel thromboxane A2/prostaglandin H2 antagonists with diminished beta-adrenergic agonist activity.
Synthesis and evaluation of trimetoquinol derivatives: novel thromboxane A2/prostaglandin H2 antagonists with diminished beta-adrenergic agonist activity.
复制标题
曲美喹诺衍生物的合成和评价：新型血栓素 A2/前列腺素 H2 拮抗剂，具有减弱的 β-肾上腺素能激动剂活性。
DOI：
10.1021/jm950896w
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Feller,DR
中科院分区：
文献类型：
--
作者：
Christoff,JJ;Bradley,L;Miller,DD;Lei,L;Rodriguez,F;Fraundorfer,P;Romstedt,K;Shams,G;Feller,DR
Trimetoquinol (TMQ,1) 是一种独特的儿茶酚胺，具有强烈的立体依赖性，可激动 β-肾上腺素能 (S≫R) 受体并拮抗血栓素 A2/前列腺素 H2(TP; R ≫ S) 受体。我们的实验室已经报道了这些受体系统中N-烷基化和三取代苄基修饰的影响。对于碘化衍生物 5，在 TP 受体系统中维持效力 (112%) 的同时，在 β-肾上腺素能受体系统中维持有限的效力（β1 为 34%，β2 为 47%）。在这项研究中，制备了几种不同的 TMQ 衍生物来探测特定受体系统特异的结合相互作用。旨在探索 TMQ 手性中心重要性的平面脒2 在每个受体系统中均显示出效力的显着损失（<1%）。同样，先前描述的N-苄基衍生物(3)与N-苯乙基衍生物4的同系物在两种受体系统中也显示出效力降低(<3％)。然而，将 TMQ 的三甲氧基苄基修饰为 4-羟基-3-硝基苄基 (7) 为 TMQ 衍生物提供了独特的先导，在 TP 受体系统中具有显着效力 (91%)，在 β-肾上腺素能受体系统中效力降低（β1 为 4%，β2 为 19%）。
Trimetoquinol (TMQ,1) is a unique catecholamine with a strong stereodependence for agonism at β-adrenergic (S≫R) and antagonism at thromboxane A2/prostaglandin H2(TP; R ≫ S) receptors. Our laboratory has reported the effects of N-alkylation and modification of the trisubstituted benzyl group in these receptor systems. For iodinated derivative5, maintaining potency in TP receptor systems (112%) was coupled with maintaining limited potency in β-adrenergic receptor systems (34% for β1and 47% for β2). In this study, several diverse TMQ derivatives were prepared to probe for binding interactions specific to a particular receptor system. Planar amidine2, which was designed to explore the importance of TMQ's chiral center, showed a dramatic loss of potency (<1%) in each receptor system. Likewise, the homologation of a previously describedN-benzyl derivative (3) to theN-phenylethyl derivative4also showed reduced potency (<3%) in both receptor systems. However, modification of the trimethoxybenzyl group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) provided a unique lead for TMQ derivatives with significant potency in TP receptor systems (91%) and reduced potency in β-adrenergic receptor systems (4% for β1and 19% for β2).