POLYPHARMACOPHORE MODEL FOR TREATMENT OF COCAINE ABUSE

可卡因滥用仍然是我们社会的一个严重问题，每年的总成本超过1000亿美元。显然，需要有效的疗法来帮助成瘾者实现戒断，然而，目前还没有有效的药物疗法。本研究方案中描述的研究涉及新型多药效单实体的设计、合成和体外表征，以及治疗可卡因滥用的药物。基本的前提是，对于可卡因滥用的治疗，一种能够治疗快感缺失和渴求的药物(药物激动剂)，并在复发时通过作用(行为拮抗)来防止可卡因的一些行为影响，将提供一种有效的治疗策略。为了实现这一目标，我们将合理地设计和优化专有的4-芳基哌啶类化合物作为单一实体，它们对多巴胺和5-羟色胺转运体(分别用于治疗快感缺乏和渴求的可卡因的药理激动剂)具有显著的抑制活性，并且还具有显著的5-HT2A拮抗剂活性(可卡因的行为拮抗作用)。这项研究利用了文献中对单胺转运体和5-HT2A受体的结构相关类似物的广泛的构效关系。拟议的商业应用：目前还没有有效的治疗可卡因成瘾的方法。这里提议的工作的成功完成最终应导致开发和销售一种治疗可卡因滥用的药物疗法。此外，所制备的化合物可能被证明对治疗其他神经学相关疾病有用，如注意力缺陷多动障碍(ADHD)、抑郁症、强迫症和相关行为障碍。

Cocaine abuse remains a significant problem in our society with total annul cost of over $100 billion. It is clear that effective therapies are needed to assist addicted individuals in achieving abstinence, however, currently no effective pharmacotherapies are available. The studies described in this research proposal involve the design, synthesis and in vitro characterization of novel polypharmacophoric single entity, treatments for cocaine abuse. The basic premise is that for the treatment of cocaine abuse, a pharmacological agent able to treat anhedonia and craving (pharmacological agonist), and to prevent some of the behavioral effects of cocaine by acting (behavioral antagonism) in the event of recidivism would provide an effective treatment stratagem. To achieve this goal we will rationally design and optimize proprietary 4- arylpiperidines as single entities that exhibit significant inhibitory activity at the dopamine and serotonin transporters (pharmacological agonists of cocaine to treat anhedonia and craving respectively) and also exhibit significant 5-HT2A antagonist activity (behavioral antagonism of cocaine). This research exploits the extensive structure activity relationships available in the literature for structurally related analogs at the monoamine transporters and the 5-HT2A receptors. PROPOSED COMMERCIAL APPLICATIONS: Currently there are no effective treatments for the treatment of cocaine addiction. The successful completion of the work proposed here should ultimately lead to the development and marketing of a pharmacotherapy for the treatment of cocaine abuse. Additionally, the compounds prepared may prove useful for the treatment of other neurologically relevant disorders such as attention deficit hyperactivity disorder (ADHD), depression, obsessive compulsive disorder and related behavioral disorders.