DEVELOPMENT OF POTENTIALLY SELECTIVE DOPAMINE AGONISTS

潜在选择性多巴胺激动剂的开发

• 批准号: 3381960
• 负责人: DAVID E NICHOLS
• 金额: $ 9.3万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3381960
• 关键词: SCH 23390; X ray crystallography; adenylate cyclase; anthracenes; benzazepines; chemical structure function; conformation; cycloheptanes; dopamine; dopamine receptor; drug design /synthesis /production; drug interactions; drug screening /evaluation; isoquinolines; phenanthridines

We have proposed that molecules containing a "beta-phenyldopamine" moiety are specific D-1 and DA1 dopamine agonists. SKF 38393 and 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline are representative of this class. SCH 3390, a specific D-I antagonist also contains a beta-phenyl-2-phenethylamine fragment. A variety of conformationally defined novel structures containing his element will be synthesized and evaluated for D-I and D-2 dopamine agonist and antagonist activity. Principal structural types to be assessed are mono nd dihydroxy-, and monohydroxy-bromo substituted trans-5,6,6a,7,9,12b-hexaydrobenzo(a)phenanthridines, and dibenzo(a,d)1,4-cycloheptadiene, and 9,10-dihydroanthracene derivatives. The racemic materials will be pharmacologically characterized, and all compounds with significant biological activity will be resolved and the absolute configuration of the more active enantiomer will be determined by x-ray crystallography. Structure-activity relationships will be developed for these classes, and attempts will be made to develop a three-dimensional topographical model of the dopamine D-1 receptor.

我们提出，含有“β-苯二胺”的分子 部分是特定的D-1和DA1多巴胺激动剂。 SKF 38393和 4-（3,4-二羟基苯基）-1,2,3,4-四氢异喹啉 该课程的代表。 SCH 3390，一种特定的D-I拮抗剂 还包含β-苯基-2-苯甲胺片段。 多样性 构象定义的新结构，其中包含他的 元素将被合成并评估D-I和D-2多巴胺 激动剂和拮抗剂活性。 主要结构类型 评估的是单二羟基 - 和单羟基溴取代 Trans-5,6,6a，7,9,12b-Hexaydrobenzo（a）妥抑素和 Dibenzo（a，d）1,4-循环二苯和9,10-二氢蒽 衍生物。 外消旋材料将在药理上是 表征，所有具有重要生物学的化合物 活动将得到解决，并绝对配置 更活跃的对映异构体将由X射线确定 晶体学。 结构活动关系将是 为这些课程开发，并尝试开发 多巴胺D-1的三维地形模型 受体。