THE COCAINE RECEPTOR--STRUCTURE/ACTIVITY RELATIONSHIPS AND LIGAND BINDING

可卡因受体——结构/活性关系和配体结合

• 批准号: 3752849
• 负责人: M J KUHAR
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752849
• 关键词: analog; chemical structure function; cocaine; dopamine; drug addiction antagonist; drug receptors; ligands; membrane transport proteins; molecular site; neurotransmitter transport; norepinephrine; psychopharmacology; receptor binding; serotonin

The goal of this project is to explore the interaction of cocaine and cocaine-like compounds with their binding sites in brain. The binding site or "receptor" thought important for the reinforcing effects of cocaine, at least in animals, is the dopamine transporter. Other effects of cocaine and its congeners are likely to be due to interaction at other sites such as other transporters. Besides developing an understanding of the interaction of cocaine with transporters, this study also reveals potent reversible and irreversible binding ligands for in vitro and in vivo studies of transporter proteins. Some compounds may be useful as treatment medications as well. Several classes of cocaine analogs were tested in binding and uptake studies at the dopamine transporter, and sometimes also at the norepinephrine and serotonin transporters. These studies were carried out using rat brain tissue although sometime human brain tissue was utilized as well. The methods employed were standard radiolabeled ligand binding techniques. Cocaine has a carbomethoxy group in the C-2 position which is required for its activity. Since oxadiazoles are excellent bioisosteres of ester groups, several oxadiazoles were synthesized and tested in binding assays. In general, these compounds showed potencies for the dopamine transporter similar to the parent esters. The most potent analog had an IC-50 of 1.6 nM, and selectivity for the dopamine transporter was high as well. These compounds may have utility as medications to treat drug abuse since replacement of the ester with the oxadiazole will produce a compound that is resistant to metabolism and long-lasting. By producing a series of compounds without the methyl group attached to the nitrogen in the ring structure, we found that demethylation enhanced affinity for the serotonin and norepinephrine transporters between 2- and 44-fold. This will be very useful when trying to design cocaine analogs selective for serotonin and norepinephrine transporters. A series of amides in the C-2 position were synthesized and tested as well. The results indicated the tertiary amides are more potent at the dopamine transporter than primary and secondary amides. Some of the compounds were both potent and highly selective for the dopamine transporter. A QSAR and CoMFA study extended knowledge from the structure-activity work and elucidated some features of the cocaine pharmacophore and provided useful predictive information. Additional compounds will be synthesized using this information.

该项目的目标是探索可卡因和 可卡因样化合物与大脑中的结合位点。 的结合 部位或“受体”，被认为对增强 可卡因，至少在动物体内，是多巴胺的转运体。 其他效果 可卡因及其同系物的相互作用很可能是由于在其他 像其他运输公司一样。 除了了解 可卡因与转运蛋白的相互作用，这项研究还揭示了 在体外和体内有效的可逆和不可逆结合配体 转运蛋白的体内研究。 一些化合物可用作 治疗药物也是。 测试了几类可卡因类似物的结合和摄取 多巴胺转运蛋白的研究，有时也在 去甲肾上腺素和血清素转运蛋白。 这些研究进行了 虽然有时人类的大脑组织 也被利用。 采用标准放射性标记配体法 绑定技术 钴在C-2位具有甲氧羰基，这是必需的。 因为它的活动。 由于恶二唑是酯的优良生物电子等排体， 组，几个恶二唑的合成和结合测试， 分析。 总的来说，这些化合物对多巴胺 类似于母体酯的转运蛋白。 最有效的类似物有一个 IC-50为1.6 nM，对多巴胺转运蛋白的选择性高 也 这些化合物可用作治疗药物， 滥用，因为用恶二唑代替酯将产生 抗代谢和持久的化合物。 通过生产一系列不含甲基的化合物， 环结构中的氮，我们发现去甲基化增强 5-羟色胺和去甲肾上腺素转运蛋白的亲和力在2-和 44倍 这将是非常有用的时候，试图设计可卡因类似物 对血清素和去甲肾上腺素转运蛋白有选择性 合成了一系列在C-2位的酰胺并进行了测试， 好. 结果表明，叔酰胺在 多巴胺转运蛋白比伯和仲酰胺。 一些 化合物对多巴胺既有效又有高度选择性， 传送器 QSAR和CoMFA研究扩展了结构-活性的知识 工作和阐明了可卡因药效团的一些特征， 提供了有用的预测信息。 其他化合物将 利用这些信息合成。