DISCOVERY OF NOVEL PHARMACOTHERAPIES--COCAINE DEPENDENCE

描述：(申请人摘要) 可卡因依赖是一个具有国家意义的问题。相当可观的 人们在研究其作用机制方面付出了很大的努力。 尽管如此，到目前为止，还没有可卡因药物疗法获得美国政府的批准。 美国食品和药物管理局。可卡因的增强特性和刺激作用如下 与其与多巴胺转运体(DAT)结合的倾向有关。 托烷类似物是DAT的有效抑制剂。在这些战略中 用于设计可卡因疗法的是化合物的开发 它们绑定到相同的站点。其中，3-苯基紫苏烷是最突出的 这些与结构活性关系的研究主要集中在 这一系列的可卡因类似物。这项提案的目标是设计 新型托烷类药物作为治疗可卡因依赖的潜在药物。 具体目标是对五个班进行生物学综合评价。 新的托烷：8-氧杂-3-芳基托烷，6-或7-羟基托烷，6-或 7-羟基-8-氧杂-3-芳基托烷、2，3-二氢-8-氮杂和8-氧-托烷，以及 6-或7-羟化的2，3-二氢-8-氮杂-和8-氧杂托烷。小心地 选定的化合物将被制备，它们对单胺的抑制作用 运输将被确定。有效和选择性的化合物将是 检测对多巴胺摄取的抑制作用和抑制作用的化合物 对多巴胺摄取影响最小的可卡因摄取将受到 行为研究。预计这些研究将导致 关于迄今未被调查的硫磺的某些方面的披露。

DESCRIPTION: (Applicant's Abstract) Cocaine dependence is a problem of national significance. A considerable effort has been expended in the study of its mechanisms of action. Notwithstanding, to date no cocaine pharmacotherapy has been approved by the FDA. The reinforcing properties and stimulant effects of cocaine are associated with its propensity to bind to the dopamine transporter (DAT). Tropane analogs are potent inhibitors of the DAT. Among the strategies utilized for the design of cocaine therapies is the development of compounds which bind to the same site. The 3-phenyltropanes have been prominent among these and structure activity relationship studies have largely focused on this series of cocaine analogs. The goal of this proposal is to design novel tropanes as potential pharmacotherapies for cocaine dependence. The specific aims are to synthesize and evaluate biologically five classes of novel tropanes: 8-oxa-3-aryltropanes, 6- or 7-hydroxytropanes, 6- or 7-hydroxy-8-oxa-3-aryltropanes, 2,3-didehydro-8-aza- and 8-oxa-tropanes, and 6-or 7-hydroxylated 2,3-didehydro-8-aza- and 8-oxatropanes. Carefully selected compounds will be prepared and their inhibition of monoamine transport will be determined. Potent and selective compounds will be assayed for inhibition of dopamine uptake and those compounds which inhibit cocaine uptake with minimal effect on dopamine uptake will be subjected to behavioral studies. It is anticipated that these studies will lead to a disclosure of SAR on aspects of the tropanes hitherto uninvestigated.