N-(ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands
N-(ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands
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DOI：
10.1021/jm030836n
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发表时间：
2003-08-28
影响因子：
7.3
通讯作者：
Stark, H
中科院分区：
文献类型：
--
作者：
Hackling, A;Ghosh, R;Stark, H
多巴胺D-3受体被认为是治疗各种神经和精神疾病的潜在治疗靶点。针对高亲和力和D-3与D-2受体偏好的配体，部分激动剂BP 897被作为先导结构。间隔段和芳基部分的变化导致n -烷基化的1-（2-甲基氧苯基）哌嗪具有显著提高的亲和力和选择性。分子模型研究支持了该结构的发展。根据多巴胺D-2和D-3受体配体的潜在生物活性构象建立了药效团模型，并对其进行了比较，以深入了解对D-2/D-3受体选择性重要的分子特性。对于本文提出的72种化合物，脂肪族或芳基间隔层的延伸和更线性的构象被证明对多巴胺D-3受体的选择性至关重要。芳基部分（苯酰胺、杂芳酰胺、芳酰亚胺）的结构多样性对（亚）纳摩尔D-3受体的亲和力有重要影响，并通过刚性芳基丙烯酰胺衍生物对其进行了优化。化合物38 (ST 280, （E)-4-碘- n-（4-（4-（2-甲氧基苯基）哌嗪-1-基）丁基）肉桂酰酰胺）显示出最有希望的药理学特征(Ki (hD(3)) = 0.5 nM；Ki (hD(2L)) = 76.4 nM；在此基础上，化合物38有望作为一种新型的放射性配体，在体外和体内进行各种与D-3受体相关的药理研究。
The dopamine D-3 receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D-3 versus D-2 receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines with markedly improved affinity and selectivity. Molecular modeling studies supported the structural development. Pharmacophore models for dopamine D-2 and D-3 receptor ligands were developed from their potentially bioactive conformation and were compared in order to get insight into molecular properties of importance for D-2/D-3 receptor selectivity. For the 72 compounds presented here, an extended and more linear conformation in the aliphatic or aryl spacers turned out to be crucial for dopamine D-3 receptor selectivity. Structural diversity in the aryl moiety (benzamides, heteroarylamides, arylimides) had a major influence on (sub)nanomolar D-3 receptor affinity, which was optimized with more rigid aryl acrylamide derivatives. Compound 38 (ST 280, (E)-4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoylamide) displayed a most promising pharmacological profile (Ki (hD(3)) = 0.5 nM; Ki (hD(2L)) = 76.4 nM; selectivity ratio of 153), and above that, compound 38 offered the prospect of a novel radioligand as a pharmacological tool for various D-3 receptor-related in vitro and in vivo investigation.