NOVEL MOLECULAR SITE FOR ANTIDOPAMINERGIC ACTION

这项研究试图加深对以下因素的理解 多巴胺受体对配体的识别及其功能影响 这样的互动。新药，这些努力的产品之一，将是 用来更好地理解 多巴胺受体在两种体外模型系统中的占位，以及 哺乳动物的神经系统。要做到这一点，我们应该将敌手的特征 与D1样多巴胺受体亚群的配基相互作用，以及 开发新的亚类选择性拮抗剂。分子模型研究， 结合选定的合成，将有助于阐明结构 赋予配体对D1样受体的效力的功能，并借此 对他们来说具有对抗性特征。这些研究将测试特定的 关于D1样受体在3D空间的药效团的假说， 对刚性化合物的初步关注，其中的“辅助芳香族” 系统处于我们假设的重要的正交构型中 D1样(如D1D5)受体的拮抗剂活性。生物学 来自大脑准备和分子表达系统的数据将 为定量结构和活性研究提供输入数据 基于计算机化的分子建模。机制(S)与功能 我们的完全激动剂二氢呋喃西定(DHX)的结果将与 可用的部分或复合激动剂(例如，SKF 38393或SKF 82958)。这个 将使用克隆细胞研究介导脱敏的因素 品系和稳定的表达系统。这项工作的假设将是 在更复杂的系统中进行测试，使用体外(例如，切片灌流) 和体内(例如，行为和微透析)技术。其他内容 努力的目标是开发和表征生物利用度 DHX的前体药物(例如亚甲二氧基DHX)或其类似物。最后，我们 将设计和合成“生物可检测”的类D_1配体。这 将包括合成和表征放射性标记的衍生物 特别是有趣的药物(最初是~3H-DHX)，还设计和 合成荧光D1-配体。最后，虽然我们的工作重点是 已经在D1样受体上，偶然发现了第二个 关注D2样受体(如D2、D3、D4)。根据最近的初步调查 数据，我们将确定某些四氢苯并菲并菲是否 衍生物对D2样突触后受体具有选择性。这 将涉及使用哺乳动物制剂的体外和体内研究，以及 后来，在只表达一种分子形式的系统中检查这些药物 这类感受器。

This research seeks to develop an understanding of the factors involved in ligand recognition by dopamine receptors, and the functional consequences of such interactions. New drugs, one product of these efforts, will be used to develop an better understanding of the functional consequences of dopamine receptor occupation in both model in vitro systems, and the mammalian nervous system. To do this we shall characterize antagonist ligand interactions with sub-populations of D1-like dopamine receptors, and develop new subclass selective antagonists. Molecular modeling studies, combined with selected syntheses, will help elucidate the structural features that give ligands potency for D1-like receptors, and lend antagonist characteristics to them. These studies will test specific hypotheses about the pharmacophore for D1 -like receptors in 3D space, with an initial focus on rigid compounds in which the "accessory aromatic" system is in the orthogonal configuration we hypothesize is important for antagonist activity at D1-like (e.g., D1 and D5) receptors. Biological data from both brain preparations and molecular expression systems will provide the input data for quantitative structure and activity studies based on computerized molecular modeling. The mechanism(s) and functional consequences of our full agonist dihydrexidine (DHX) will be compared to available partial or complex agonists (e.g., SKF 38393 or SKF 82958). The factors that mediate desensitization will be studied using clonal cell lines and stable expression systems. Hypotheses from such -work will be tested in more complex systems, using both in vitro (e.g., slice perfusion) and in vivo (e.g., behavioral and microdialysis) techniques. Additional efforts will be aimed at developing and characterizing bioavailable prodrugs of DHX (e.g., methylenedioxyDHX) or its analogs. Finally, we shall design and synthesize D1-like ligands that are "biodetectable". This will include synthesizing and characterizing radiolabeled derivatives of specifically interesting drugs (initially 3H-DHX), and also to design and synthesize fluorescent D1-ligands. Finally, Although the focus of our work has been on D1-like receptors, serendipitous findings have led to a second focus on D2 like (e.g., D2, D3, D4) receptors. Based on recent preliminary data, we shall determine if certain tetrahydrobenzophenanthridine derivatives have selectivity for D2-like post-synaptic receptors. This will involve in vitro and in vivo studies using mammalian preparations, and later, examining these drugs in systems expressing only one molecular form of this class of receptors.