NOVEL MOLECULAR SITE FOR ANTIDOPAMINERGIC ACTION

抗多巴胺能作用的新型分子位点

• 批准号: 2244995
• 负责人: Richard B Mailman
• 金额: $ 29.04万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2244995
• 关键词: SCH 23390; affinity chromatography; amygdala; antipsychotic agents; benzazepines; brain metabolism; chemical structure function; clone cells; computer simulation; corpus striatum; cyclic AMP; dopamine receptor; drug design /synthesis /production; drug receptors; fluorescent dye /probe; high performance liquid chromatography; laboratory rat; microdialysis; pharmacokinetics; phenanthridines; prodrugs; psychopharmacology; radiotracer; receptor binding; receptor coupling; receptor expression; receptor sensitivity; tranquilizer

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.

这项研究旨在加深对影响因素的理解 多巴胺受体的配体识别及其功能后果 的此类互动。 新药是这些努力的产物之一，将 用于更好地理解功能后果 两个模型体外系统中的多巴胺受体占据，以及 哺乳动物的神经系统。 为此，我们将描述对手 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， 与选定的合成相结合，将有助于阐明结构 赋予 D1 样受体配体效力的特征，并借以 他们的拮抗特征。 这些研究将测试具体的 关于 3D 空间中 D1 样受体药效团的假设 最初关注刚性化合物，其中“辅助芳香族” 系统处于正交配置，我们假设对于 D1 样（例如 D1 和 D5）受体的拮抗剂活性。 生物 来自大脑制剂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 基于计算机分子模型。 机制和功能 我们的完全激动剂二羟西定 (DHX) 的后果将与 可用的部分或复合激动剂（例如 SKF 38393 或 SKF 82958）。 这 将使用克隆细胞研究介导脱敏的因素 系和稳定表达系统。 此类工作的假设将是 使用体外（例如切片灌注）在更复杂的系统中进行测试 和体内（例如行为和微透析）技术。 额外的 努力的目标是开发和表征生物可利用的 DHX(例如亚甲二氧基DHX)或其类似物的前药。 最后，我们 应设计并合成“可生物检测”的 D1 样配体。 这 将包括合成和表征放射性标记的衍生物 特别有趣的药物（最初是 3H-DHX），以及设计和 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 重点关注 D2 样（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进行体外和体内研究，并且 随后，在仅表达一种分子形式的系统中检查这些药物 属于此类受体。