Christoff J J, Bradley L, Miller D D, Lei L, Rodriguez F, Fraundorfer P, Romstedt K, Shams G, Feller D R
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210, USA.
J Med Chem. 1997 Jan 3;40(1):85-91. doi: 10.1021/jm950896w.
Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at beta-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 derivative 5, maintaining potency in TP receptor systems (112%) was coupled with maintaining limited potency in beta-adrenergic receptor systems (34% for beta 1 and 47% for beta 2). In this study, several diverse TMQ derivatives were prepared to probe for binding interactions specific to a particular receptor system. Planar amidine 2, 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 described N-benzyl derivative (3) to the N-phenylethyl derivative 4 also 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 beta-adrenergic receptor systems (4% for beta 1 and 19% for beta 2).
曲美托喹诺（TMQ，1）是一种独特的儿茶酚胺，对β-肾上腺素能受体激动作用具有强烈的立体依赖性（S >> R），对血栓素A2/前列腺素H2（TP；R >> S）受体具有拮抗作用。我们实验室已经报道了在这些受体系统中N-烷基化和三取代苄基修饰的作用。对于碘化衍生物5，在TP受体系统中保持活性（112%）的同时，在β-肾上腺素能受体系统中的活性有限（β1为34%，β2为47%）。在本研究中，制备了几种不同的TMQ衍生物，以探究特定受体系统特有的结合相互作用。为探究TMQ手性中心的重要性而设计的平面脒2，在每个受体系统中活性都显著丧失（<1%）。同样，将先前描述的N-苄基衍生物（3）同系化为N-苯乙基衍生物4，在两个受体系统中的活性也降低了（<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衍生物提供了一个独特的先导化合物，其在TP受体系统中具有显著活性（91%），在β-肾上腺素能受体系统中的活性降低（β1为4%，β2为19%）。
