Serotonergic properties of spiroxatrine enantiomers.
Serotonergic properties of spiroxatrine enantiomers.
复制标题
螺沙汀对映体的血清素能特性。
DOI：
10.1021/jm00118a017
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发表时间：
1988
影响因子：
7.3
通讯作者：
Nelson,DL
中科院分区：
文献类型：
--
作者：
Nikam,SS;Martin,AR;Nelson,DL
精神安定药螺哌隆（1）已被证明在鉴定假定的5-羟色胺（5-HT）受体方面非常有用。因此，5-受体已根据其对1的亲和力分为亚型：5-HTja位点具有高亲和力，而5-HT 1B位点具有低亲和力。然而，由于1对5-HT 2（以及D2-多巴胺能）受体的高亲和力，其用于5-位点的药理学表征的有用性受到限制。1的类似物，（i）-spiroxatrine（2），对5-HT 1A受体的亲和力高得多，对5-HT 2受体的亲和力低得多。本文报道了（？）-（+）-和（S）-（-）-spiroxatrine对映体及其对几种5-HT受体和D2-多巴胺能和肾上腺素能受体的评价在寻找5-受体的选择性拮抗剂时，最初研究的化合物是神经安定药spiperone（1）。除了对D2和5-HT 2受体具有高亲和力外，螺哌隆还区分5-结合位点的亚型，对5-位点具有高亲和力，对5-HT 1B位点具有低亲和力。1从Janssen实验室获得的一系列与螺哌隆相关的类似物在5-HT 1A、5-HT 1B和5-HT 2结合位点上的效力进行了检查，试图找到对5-HT 1A位点具有更大选择性的药物。2这些化合物中最有效和选择性最强的是spiroxatrine（2），它在5-HT 1A和5-HT 1B位点之间表现出很好的区分性，对前者的效力是前者的75000倍。它在5-HT 1A位点的效力也是5-HT 2位点的30倍。为了进一步研究2的选择性，我们立体特异性地制备了R-（+）和S-（-）对映体，并检测了它们与5-HT 1A、5-HT 1B、5-HT 2和D2-多巴胺能和-肾上腺素能受体的结合。
The neuroleptic drug spiperone (1) has proven very useful in the characterization of putative serotonin (5-hydroxytryptamine, 5-HT) receptors. Thus, 5-receptors have been divided into subtypes based on their affinities for 1: 5-HTja sites have high affinity, while 5-HT1B sites have low affinity. However, the usefulness of 1 for the pharmacological characterizationof 5-sites is limited because of its high affinity for 5-HT2 (as well as D2-dopaminergic) receptors. A close analogue of 1,(i)-spiroxatrine (2), has much higher affinity for 5-HT1A receptors and much lower affinity for 5-HT2 receptors. We report here the stereospecific synthesis of (/?)-(+)-and (S)-(-)-spiroxatrine enantiomers and their evaluation at several 5-HT receptors and D2-dopaminergic and-adrenergic receptors.In a search for selective antagonists for 5-receptors, the compound initially studied was the neuroleptic drug spiperone (1). In addition to having high affinity for D2 and 5-HT2 receptors, spiperone also distinguishes between the subtypes of 5-binding sites, havinghigh affinity for 5-sites and low affinity for 5-HT1B sites. 1 A series of analogues related to spiperone obtained from Janssen Laboratories were examined for their potencies at 5-HT1A, 5-HT1B, and 5-HT2 binding sites in an attempt to find an agent with greater selectivityfor 5-HT1A sites. 2 The most potent andselective of these compounds was spiroxatrine (2), which exhibits excellent discrimination between 5-HT1A and 5-HT1B sites, being 75000 times more potent at the former. It also was 30 times more potent at 5-HT1A sites than at 5-HT2 sites. In order to further investigate the selectivity of 2, we have stereospecifically prepared the R-(+) and S-(-) enantiomers and examined their binding at 5-HT1A, 5-HT1B, 5-HT2, and D2-dopaminergic and-adrenergic receptors.