多巴胺D2拮抗剂的药效团中掺入丁苯酮和相关化合物。

Drug design and discovery Pub Date : 1997-08-01
M Froimowitz, V Cody
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引用次数: 0

摘要

本研究试图将一类重要的非三环抗精神病药物丁苯酮纳入先前提出的三环多巴胺D2受体拮抗剂配体的药效团模型。利用MM3-92程序对具有代表性的丁苯酮类化合物spiperone以及构象自由度较为有限的相关化合物milenperone和R48455进行了构象能计算。用MM3-92计算方法对27个螺环酮的构象进行了评估,其中9个构象在1.1 kcal/mol的全球最小值范围内,表明该化合物的柔韧性。对20种丁苯酮的晶体结构进行了构象分析,得到了6种不同的构象。所有的能量最小化构象都以最小二乘的方式叠加在洛沙平上,作为相对刚性的典型D2拮抗剂,并且在一个晶体结构中观察到一对镜像构象,发现它们是最合适的。然而,这是不可能区分这两种构象,因为它们同样适合药效团模型。发现丁苯酮的对氟基团和羰基基团分别与洛沙平的氧原子和氯原子最对应。milenperone和R48455的构象也符合spiperone的两种假定的生物活性形式和药效团模型。对临床使用的抗精神病药物molindone也进行了构象能计算,它可能与丁苯酮有关,因为两者都有一个羰基毗邻芳香环。提出了一种假定的莫林酮生物活性形式,这与莫林酮的刚性类似物piquindone的结构有关。所有化合物均与药效团模型完全一致。然而,如前所述,铵态氮与相关芳环中心的距离有很大的变化,本研究中最极端的情况是R48455,其距离为7.2 A。本研究的结果也应该与新型非典型抗精神病药物的结构有关,如利培酮,它似乎是丁苯酮的类似物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The incorporation of butyrophenones and related compounds into a pharmacophore for dopamine D2 antagonists.

This study is an attempt to incorporate the butyrophenones, an important class of nontricyclic antipsychotic drugs, into a previously proposed pharmacophore model of tricyclic dopamine D2 receptor antagonist ligands. Conformational energy calculations were performed using the MM3-92 program on spiperone, as a representative butyrophenone, and milenperone and R48455, as related compounds with more limited conformational freedom. Twenty seven conformers were evaluated for spiperone with MM3-92 calculations and nine of these were within 1.1 kcal/mole of the global minima indicating the flexibility of the compound. A conformational analysis of twenty crystal structures of butyrophenones was also performed and six distinct conformers were represented. All of the energy minimized conformers of spiperone were superimposed in a least squares sense onto loxapine as a relatively rigid, typical D2 antagonist and a pair of mirror image conformers, which are observed in one crystal structure of spiperone, were found to be the best fit. However, it was not possible to discriminate between these two conformers since they fit the pharmacophore model equally well. The para-fluoro and carbonyl group of the butyrophenones were found to correspond best to the oxygen and chlorine atoms of loxapine, respectively. The conformations of milenperone and R48455 were also consistent with the two putative biologically active forms of spiperone and the pharmacophore model. Conformational energy calculations were also performed on molindone, an antipsychotic drug in clinical use, which can be related to the butyrophenones since both have a carbonyl group adjacent to an aromatic ring. A putative biologically active form was proposed for molindone and this was related to the structure of piquindone, a rigid analog of molindone. All of the compounds were found to be entirely consistent with the pharmacophore model. However, as previously found, there is great variability in the distance between the ammonium nitrogen and the center of the relevant aromatic ring with the most extreme case in the present study being R48455 where the distance is 7.2 A. The results of the present study should also be relevant to the structures of novel, atypical antipsychotic drugs such as risperidone which appear to be analogs of the butyrophenones.

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