NOVEL MOLECULAR SITE FOR ANTIDOPAMINERGIC ACTION

这项研究旨在了解参与的因素， 多巴胺受体的配体识别，以及功能性后果 这样的互动。 这些努力的产物之一，新药物， 用于更好地理解 在两种体外系统模型中，多巴胺受体占据， 哺乳动物的神经系统 要做到这一点，我们将描绘拮抗剂 配体与D1样多巴胺受体亚群的相互作用，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 这些特征赋予D1样受体配体效力， 对他们来说，这是一种对抗性的特征。 这些研究将测试特定的 关于3D空间中D1样受体药效团的假设， 最初的重点是刚性化合物，其中“辅助芳族” 系统处于我们假设重要的正交配置中， 在D1样的拮抗剂活性（例如，D1和D5）受体。 生物 来自大脑制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 基于计算机化分子模型。 机制和职能 我们的完全激动剂dihydrexidine（DHX）的后果将与 可用的部分或复合激动剂（例如，SKF 38393或SKF 82958）。 的 将使用克隆细胞研究介导脱敏的因素。 系和稳定的表达系统。 假设从这样的工作将是 在更复杂的系统中进行测试，使用体外（例如，切片灌注） 并且在体内（例如，行为和微透析）技术。 额外 将努力开发和表征生物可利用的 DHX的前药（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D1样配体。 这 将包括合成和表征放射性标记的衍生物， 特别感兴趣的药物（最初是3 H-DHX），并设计和 合成荧光D1-配体。 最后，虽然我们的工作重点 一直在D1样受体上，偶然的发现导致了第二个 专注于D2（例如，D2、D3、D4）受体。 根据近期初步 数据，我们将确定某些四氢苯并菲啶 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， 之后，在仅表达一种分子形式的系统中检测这些药物， 这类受体的基因。

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.