DISCOVERY OF NOVEL PHARMACOTHERAPIES--COCAINE DEPENDENCE

描述：（申请人摘要） 依赖性是一个具有全国性意义的问题。 相当 已努力研究其作用机制。 尽管如此，迄今为止，尚未有可卡因药物治疗被批准， FDA. 可卡因的强化特性和刺激作用是 与其结合多巴胺转运蛋白（DAT）的倾向有关。 托烷类似物是DAT的有效抑制剂。 用于设计可卡因疗法的是开发化合物， 它们结合在同一个位点上 3-苯基托烷在其中一直很突出， 这些和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 该提案的目标是设计 作为可卡因依赖的潜在药物疗法的新型托烷。 具体目标是对五类生物进行综合评价 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，2，3-二氮杂-8-氮杂-和8-氧杂-托烷，和 6-或7-羟基化的2，3-二氢-8-氮杂-和8-氧杂阿托品。 仔细 将制备选定的化合物，并将它们对单胺的抑制作用 运输将被确定。 有效的和选择性的化合物将是 测定对多巴胺摄取的抑制作用和那些抑制多巴胺摄取的化合物 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 关于迄今为止未调查的托烷方面的SAR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.