THERAPEUTICS FOR COCAINE DEPENDENCE--NATURAL PRODUCTS

治疗可卡因依赖的药物：天然产品 大鼠中脑边缘区多巴胺受体亚型的刺激 大脑似乎与寻求可卡因直接相关 行为。因此，药物制剂的发展 选择性地与多巴胺受体亚型相互作用有可能 为可卡因成瘾的不同阶段提供药物治疗， 包括激发、强化、渴望、复发和/或欣快感。近期 研究表明，类似D-2的多巴胺受体刺激可能在 寻求进一步加强可卡因的动机，而类似于d1 多巴胺受体刺激可能会减弱增强(赛尔夫等人， 1996年)。 天然植物产品在过去是一种丰富的 药物治疗剂的发展。因此，很可能就是 具有多巴胺能活性的天然化合物可以通过以下方法进行鉴定 测试天然产品的萃取物。这项拨款申请的目标是 鉴定在第一天有活性的天然产物的提取物- 类似和/或D2样多巴胺受体。 活性提取物的初步药理特性以确定 五种D1样化合物提取物的药理选择性 (D1a和D1b)和类D2(D2，D3和D4)多巴胺受体亚型和 以确定活性成分是否是拮抗剂、激动剂、 D1样和D2样各自的部分激动剂或反向激动剂 多巴胺受体亚型。纯化和结构鉴定 激活的组件。这个应用程序的最终目标是识别小说 先导化合物可用于开发天然的、半 合成的或合成的化合物，如：D1a和D1b 多巴胺受体选择性激动剂或部分激动剂或D3多巴胺 受体亚型选择性拮抗剂。

Therapeutics for Cocaine Dependence: Natural Products Stimulation of dopamine receptor subtypes in the mesolimbic area of the brain appears to be directly associated with the cocaine-seeking behaviors. Therefore, the development of pharmacologic agents that selectively interact with dopamine receptor subtypes has the potential for yielding a pharmacotherapy for the various stages for cocaine addiction, including priming, reinforcement, craving, relapse and/or euphoria. Recent studies suggest that D-2 like dopamine receptor stimulation may mediate the incentive to seek further cocaine reinforcement, while D1-like dopamine receptor stimulation may attenuate reinforcement (Self et al., 1996). Natural plant products have served in the past as a rich source for the development of pharmacotherapeutic agents. Therefore, it is probably that natural compounds having dopaminergic activity can be identified by testing extracts of natural products. The goal of this grant application is to identify the extracts of natural products which have activity at D1- like and/or D2-like dopamine receptors. Initial pharmacologic characterization of the active extracts to determine the pharmacologic selectivity of the extract for each of the five D1-like (D1a and D1b) and D2-like (D2, D3, and D4) dopamine receptor subtypes and to determine whether the active component is an antagonist, agonist, partial agonists or inverse agonist at each of the D1-like and D2-like dopamine receptor subtypes. Purification and structural identification active components. The final goal of this application is to identify novel lead compounds that can be used for the development of natural, semi- synthetic or synthetic compounds that are either D1-like (D1a and D1b) dopamine receptor selective agonists or partial agonists or D3 dopamine receptor subtype selective antagonists.