Discovery of Novel Pharmacotherapies: Cocaine Dependence

描述(申请人提供)：可卡因依赖是一个国家问题。在过去的十年里，对可卡因依赖的化学和药理学的理解有了长足的进步。尽管如此，FDA还没有批准可卡因药物疗法。一些先导化合物正在接受药理学评估，作为潜在的治疗剂。 可卡因的增强特性和刺激作用与其与单胺转运体结合的倾向有关。该项目的目标是设计治疗可卡因依赖的潜在药物疗法。我们将集中于了解配体和单胺类神经递质摄取系统之间的相互作用。我们建议扩大我们的搜索范围，寻找与DAT和SERT机制结合但对多巴胺(DA)摄取干扰最小的化合物，寻找起效慢且持续时间长的化合物，以及基于机制的可卡因结合抑制剂。我们将重点介绍三类化合物：8-氧杂双环[3，2，1]辛烷(氧杂托烷)、8-氮杂双环[3，2，1]辛烷(托烷)和吡喃酮类似物。 具体目标是： (I)非氮托烷类似物，(Ii)6-和7-羟化8-氮杂托烷前药，(Iii)6-和7-羟化8-氧托品(En)，(Iv)与可卡因部位不可逆结合的多巴胺节约型可卡因拮抗剂的合成和评价，(V)3-杂二芳基托烷。(Vi)吡喃酮的类似物。

DESCRIPTION (provided by applicant): Cocaine dependence is a problem of national significance. In the past decade there has been a considerable advance in the understanding of the chemistry and pharmacology of cocaine dependence. Notwithstanding, no cocaine pharmacotherapy has yet been approved by the FDA. A number of lead compounds are undergoing pharmacological evaluation as potential therapeutic agents. Cocaine's reinforcing properties and stimulant effects are associated with its propensity to bind to monoamine transporters. The goal of this project is to design potential pharmacotherapies for cocaine dependence. We will focus on the development of an understanding of the interaction between ligand and monoamine neurotransmitter uptake systems. We propose to expand our search for compounds that bind to DAT and SERT mechanisms but disturb dopamine (DA) uptake minimally, for compounds with slow onset and long duration of action, and for mechanism-based inhibitors of cocaine binding. We will focus on three classes: 8-oxabicyclo[3,2,1]octanes (oxatropanes), 8-azabicyclo[3,2,1]octanes (tropanes) and pyrovalerone analogues. The Specific Aims are: Synthesis and evaluation of (i) non-nitrogen tropane analogs, (ii) 6- and 7 hydroxylated 8-azatropane prodrugs, (iii) 6- and 7-hydroxylated 8-oxatropan(en)es, (iv) dopamine sparing cocaine antagonists that bind irreversibly to the cocaine site, (v) 3-heterobiaryltropanes. (vi) analogues of pyrovalerone.