THERAPEUTICS FOR COCAINE DEPENDENCE--NATURAL PRODUCTS

药物依赖的治疗：天然产品 中脑边缘区多巴胺受体亚型的刺激 大脑似乎直接与寻找可卡因有关 行为。因此，开发药物制剂， 选择性地与多巴胺受体亚型相互作用， 产生了可卡因成瘾各个阶段的药物疗法， 包括引发、强化、渴望、复发和/或欣快。最近 研究表明，D-2样多巴胺受体刺激可能介导 寻求进一步可卡因强化的动机，而D1样 多巴胺受体刺激可以减弱强化（Self等， 1996年）。 天然植物产品在过去一直是 药物制剂的开发。因此，很可能是， 具有多巴胺能活性的天然化合物可以通过 测试天然产品的提取物。这项拨款申请的目的是 是鉴定在D1-D2具有活性的天然产物的提取物， 和/或D2类多巴胺受体。 活性提取物的初步药理学表征，以确定 提取物对五种D1样蛋白中每一种的药理学选择性 (D1a和D1 b）和D2样（D2、D3和D4）多巴胺受体亚型， 为了确定活性成分是否是拮抗剂，激动剂， 在D1样和D2样中的每一个处的部分激动剂或反向激动剂 多巴胺受体亚型纯化及结构鉴定 活性成分本申请的最终目标是确定新的 铅化合物，可用于开发天然，半， 合成的或合成的化合物是D1样的（D1 a和D1 b） 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.