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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Structure-activity relationship of trihexyphenidyl analogs with respect to the dopamine transporter in the on going search for a cocaine inhibitor.
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Structure-activity relationship of trihexyphenidyl analogs with respect to the dopamine transporter in the on going search for a cocaine inhibitor.

机译：在不断寻找可卡因抑制剂中，三己基苯基类似物相对于多巴胺转运蛋白的构效关系。

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摘要

A series of trihexyphenidyl (THP) analogs were used to search for a derivative that could serve as a cocaine inhibitor. A compound that blocks binding of the cocaine analog carboxyfluorotropane (CFT), allows dopamine uptake and exhibits low side effects could serve as a good candidate for that purpose. All analogs were tested for the extent to which they inhibit CFT binding, dopamine uptake and n-methyl scopolamine (NMS) binding. Several structure-function relationships emerged. Methylation/halogenation of THP's benzene ring enhanced the compound's ability to block CFT binding in comparison to its ability to block dopamine uptake (5a-e). Replacement of the cyclohexyl ring with a benzene ring tended to create compounds that had lower affinities to the dopamine transporter (7b compared to THP, 7d compared to 5h, 7c compared to 8c) and modification of THP's piperidine ring tended to enhance affinity to the dopamine transporter (5f-h, 8a, 8c). One analog (5f) that showed little muscarinic activity indicating that it would probably have few side effects was investigated for its effects as an in vivo cocaine inhibitor. However, it showed few antagonistic effects in vivo. Nevertheless, this work greatly elucidates the structure-function relationships required for potential cocaine inhibitors and so lays out promising directions for future research.
机译：一系列的三己基苯基（THP）类似物用于寻找可卡因抑制剂的衍生物。阻止可卡因类似物羧基氟代烷（CFT）结合，允许多巴胺摄取并表现出低副作用的化合物可以用作该目的的良好候选者。测试所有类似物抑制CFT结合，多巴胺摄取和正甲基东pol碱（NMS）结合的程度。出现了几种结构功能关系。与THP苯环的甲基化/卤化相比，该化合物阻断CFT结合的能力与其阻断多巴胺摄取的能力相比有所提高（5a-e）。用苯环取代环己基环往往会产生对多巴胺转运蛋白的亲和力较低的化合物（与THP相比为7b，与5h相比为7d，与8c相比为7c），THP哌啶环的修饰往往会增强对多巴胺的亲和力转运车（5f-h，8a，8c）。研究了一种几乎没有毒蕈碱活性的类似物（5f），这表明它可能具有很少的副作用，作为其体内可卡因抑制剂的作用已得到研究。但是，它在体内几乎没有拮抗作用。然而，这项工作极大地阐明了潜在可卡因抑制剂所需的结构-功能关系，因此为今后的研究奠定了有希望的方向。

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