Discovery of Novel Pharmacotherapies: Cocaine Dependence

说明（由申请人提供）：可卡因依赖是一个具有国家意义的问题。在过去十年中，对可卡因依赖性的化学和药理学的认识有了相当大的进展。 尽管如此，FDA尚未批准任何可卡因药物治疗。许多先导化合物作为潜在的治疗剂正在进行药理学评价。 辅酶A的增强特性和刺激作用与其结合单胺转运蛋白的倾向有关。该项目的目标是为可卡因依赖设计潜在的药物疗法。我们将专注于了解配体和单胺神经递质摄取系统之间的相互作用的发展。我们建议扩大我们的搜索化合物，结合DAT和SERT机制，但干扰多巴胺（DA）的摄取最低限度，为化合物的起效缓慢，持续时间长，并为机制为基础的抑制剂可卡因结合。我们将重点讨论三类：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）和吡咯戊酮类似物。 具体目标是： 合成和评价（i）非氮托烷类似物，（ii）6-和7-羟基化的8-氮杂托烷前药，（iii）6-和7-羟基化的8-氧杂托烷（烯），（iv）不可逆地与可卡因位点结合的多巴胺保留可卡因拮抗剂，（v）3-杂联芳基托烷。(vi)吡咯戊酮的类似物。

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.