NOVEL SEROTONIN UPTAKE INHIBITOR LIGANDS

5-羟色胺（5-HT）转运蛋白复合物是一种位于 中枢神经系统中多巴胺能神经元的突触前侧 参与调节5-HT的浓度（摄取） 在突触间隙里这种蛋白质含有一个结合位点， 血清素，被认为在各种精神疾病中起着关键作用。 健康失调5-HT结合位点可以被阻断。这个网站有 被证明是许多商业的目标， 选择性抗抑郁药和滥用药物，包括 可卡因我们的长期目标是进一步阐明 5-羟色胺摄取抑制剂结合位点。该研究将发展 新的化学探针，并进行计算建模研究， 为了完善一个初步的三维模型的 并采用计算机辅助的三- 三维定量构效关系 比较分子场分析以绘制5-HT摄取 结合位点为了实现这些目标，我们的具体目标包括： I）半刚性的和非刚性的聚乙二醇的合成和体外结合评估。 柔性喹啉基-和吲哚基苯基烷基胺分子; 2） 5-HT摄取时体外结合的合成和评估 苯基氮杂卓并吲哚配体的受体以及地诺-12- 羟基磷灰石;和3）计算机辅助建模， 受模板强制影响的活性类似物方法，构象 分析了基于配体的结构和改进 药效团5-HT摄取模型，然后利用 改进的药效团模型在3D-QSAR中的应用 比较分子场分析得到的结合位点图 可能被证明是潜在的有用的结合亲和力预测 将用于其他结构新颖的设计值 具有增强的生物化学性质和高结合的药物 5-羟色胺摄取位点的亲和力。由此产生的新药 设计范例可以作为新的疗法或作为 5-羟色胺相关精神疾病的诊断工具。

The serotonin (5-HT) transporter complex is a protein located on the pre-synaptic side of serotonergic neurons in the central nervous system and is involved in regulating concentrations of 5-HT (uptake) in the synaptic cleft. This protein contains a binding site for serotonin and is thought to play a critical role in a variety of mental health disorders. The 5-HT binding site can be blocked. This site has been-shown to be the target of many of the commercial, highly selective antidepressants and also of drugs of abuse, including cocaine. Our long-term objective is to further elucidate the structure of the 5-HT uptake inhibitor binding site. The study will develop new chemical probes and perform computational modeling studies in order to refine a prelminary three-dimensional model of the inhibitorypharmacophore and employ computer-aided three- dimensional quantitative structure-affinity relationship (3D-QSAR) comparative molecular field analyses to map the 5-HT uptake binding site. To accomplish these goals, our specific aims encompass I)the syntheses and in vitro binding evaluations of semi-rigid and flexible quinolyl- and indolylphenylalkylamine molecules; 2) the syntheses and assessments of in vitro binding at the 5-HT uptake receptor of phenylazepinoindole ligands and also dinor-12- hydyroxyibogaine; and 3) computer-aided modeling employing an active analog approach effected by template forcing, conformational analyses for construction and refinement of the ligand based pharmacophore 5-HT uptake model followed by the utilization of a refined pharmacophore model for the application of a 3D-QSAR comparative molecular field analysis. The resultant binding site map may prove to be potentially useful for its binding affinity prediction value which will be used for the design of other structurally novel drugs with enhanced biochemical properties and high binding affinities for the serotonin uptake site. New drugs afforded from this design paradigm may find application as new therapies or as diagnostic tools in serotonin related mental health disorders.