COMBINATORIAL PHARMACOTHERAPIES FOR COCAINE DEPENDENCE

描述：(申请人摘要) 可卡因在美国的过度使用导致了巨大的社会和 经济损失。临床医生曾尝试使用药理学 通过阻断可卡因的影响来减少可卡因渴望的干预 “交感神经风暴”，但理想的药物治疗一直没有 开发、设计和合成专门设计的新药 为了治疗可卡因滥用，迫切需要。因为 多巴胺转运体(DAT)已被确定为相关的大分子 启动可卡因自我管理，开发新方法 设计、合成和获得高亲和力拮抗剂(或部分 激动剂)不抑制多巴胺摄取和/或 刺激多巴胺摄取将构成一种重要的新药物疗法 在可卡因滥用的医疗治疗中。这样的药物可能会非常 如果医生给患者注射，对可卡因成瘾者也有帮助 正在接受心理咨询。为了获得这样一种人类治疗方法 将需要筛选大量潜在的DAT拮抗剂(或 部分拮抗者)。我们研究的长期目标是发展 选择性、无毒的高亲和力拮抗剂(或部分拮抗剂) 具有长时间作用的人类多巴胺转运体可以阻止 可卡因的增强和刺激特性。 建议的研究分为四个主要部分：1)设计和 定向有机化学组合文库的合成及合成 定向假肽组合文库，2)评价 定向组合文库作为酶的拮抗剂(或部分激动剂) 基因表达的人HDAT及其摄取抑制实验，3) 进一步定义第1节、第2节和第4节中确定的活性化合物) HDAT拮抗剂相对HDAT的选择性评价 去甲肾上腺素和5-羟色胺转运体，并检查关键药物 以及“优化”化合物的药代动力学特性。具体的 第2节的目的包括通过以下方式对图书馆进行动态评估 HDAT结合和多巴胺摄取的筛查。的具体目标 第四节包括优化药物的大规模合成。 候选人，针对其他运输者进行筛选，并测试 最具活性的化合物的药学特性。动物行为 评估可预测体内疗效。这项研究将提供一个 了解HDAT的结构和药用性能 对抗者。这项工作将使我们对 停止滥用可卡因所需的人类药物。

DESCRIPTION: (Applicant's Abstract) Cocaine overuse in the United States has resulted in enormous social and economic loss. Clinicians have attempted to use pharmacological intervention to decrease cocaine craving by blocking the affects of the "sympathetic neural storm", but the ideal pharmacotherapy has not been developed and design and synthesis of new medications designed specifically for the purpose of treating cocaine abuse is urgently needed. Because the dopamine transporter (DAT) has been identified as the relevant macromolecule for initiating cocaine self-administration, development of novel approaches to design, synthesize and procure high affinity antagonists (or partial agonists) of the DAT that do not inhibit dopamine uptake and/or that stimulate dopamine uptake would constitute an important new pharmacotherapy in the medical treatment of cocaine abuse. Such a medication could be very helpful to a cocaine addict if administered by a doctor to a patient also undergoing psychological counseling. To obtain such a human therapeutic will require the screening of large numbers of potential DAT antagonists (or partial antagonist). The long term goal of our research is to develop selective, nontoxic high affinity antagonists (or partial antagonists) of the human dopamine transporter with long duration of action that blocks the reinforcing and stimulant properties of cocaine. The proposed studies are divided into four major sections: 1) Design and synthesis of directed organic chemical combinatorial libraries and synthesis of directed pseudopeptide combinatorial libraries, 2) Evaluation of the directed combinatorial libraries as antagonists (or partial agonists) of the cDNA-expressed human hDAT as well as in uptake inhibition experiments, 3) Further define the active compounds identified in section 1 and 2, and 4) Evaluation of the selectivity of the antagonists for the hDAT relative to the norepinephrine and serotonin transporter, and examine key pharmaceutical and pharmacokinetic properties of the "optimized" compounds. The specific aims of section 2 include the kinetic evaluation of the libraries by screening for hDAT binding and dopamine uptake. The specific aims of section 4 include the large scale synthesis of the optimized drug candidates, screening against other transporter and testing the pharmaceutical properties of the most active compounds. Animal behavioral assessment may predict in vivo efficacy. The study will provide an understanding of the structural and pharmaceutical properties of hDAT antagonists. The work will lead to new insight into the preparation of human medications necessary in the cessation of cocaine abuse.