Development of Potential Treatment Medications for Drug Abuse

描述(由申请人提供)：本申请的主要目标是发现和开发治疗药物滥用的药物。此外，我们预计所开发的化合物还将作为生化探针，有助于更好地了解可卡因、苯丙胺成瘾和戒断的生化和分子机制。该提案的最初目标是设计、合成和评估多巴胺(DA)、5-羟色胺(5-HT)和去甲肾上腺素(NE)释放剂。到目前为止，对兴奋剂成瘾的“激动剂”疗法的大部分努力都集中在发现选择性多巴胺摄取阻滞剂上。然而，越来越多的证据表明，在戒断过程中，可能需要双DA/5-羟色胺选择性或非选择性化合物来“纠正”刺激剂诱导的全部缺陷。自最初的拨款申请以来发表的实验结果也表明，释放剂作为一类可能是有效的突触激动剂治疗。这三个神经递质系统之间的活动的最佳平衡尚不清楚，但假设DAR能活动必须与其他活动的某种组合存在。因此，该应用程序的主要目标是进一步开发在初始项目期间产生的双DA/5HT和非选择性的“通用”释放器导联。这些化合物也可能用于治疗其他精神疾病，如抑郁、焦虑和压力。目标化合物将是有望穿透中枢神经系统的小分子，具有合理的稳定性，因此它们将成为有用的药物，并可用作体外和体内的探针。 与公共健康相关：兴奋剂滥用和成瘾仍然是美国的一个主要社会问题。越来越多的证据表明，对抗兴奋剂成瘾的最好方法之一是激动剂方法，即药物取代慢性兴奋剂造成的生化缺陷。这种方法可能是解决戒断期间观察到的广泛症状以及复发吸毒行为的冲动的唯一途径。双多巴胺/5-羟色胺释放剂代表了这种激动剂治疗的一种方法，并将在本研究计划中开发。

DESCRIPTION (provided by applicant): The major goal of this application is to discover and develop medications for the treatment of substance abuse. Furthermore, we expect that the compounds developed will also serve as biochemical probes useful in gaining a better understanding of the biochemical and molecular mechanisms of cocaine, and amphetamine addiction and withdrawal. The initial objective of this proposal is to design, synthesize, and evaluate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) releasers. To date, most efforts towards an "agonist" therapy of stimulant addiction have concentrated on the discovery of selective DA uptake blockers. However increasing evidence shows that dual DA/5-HT selective or non-selective compounds may be required to "correct" the totality of stimulant-induced deficits during withdrawal. Experimental results published since the original grant application also suggests that releasers as a class may be effective synaptic agonist treatments. The optimal balance of activity between these three neurotransmitter systems is not known; however it is assumed that DAergic activity must be present with some combination of other activity. Thus, the primary objective of this application is to further develop the dual DA/5HT and non-selective "universal" releaser leads generated during the initial project period. These compounds may also be useful for treating other psychiatric disorders such as depression, anxiety, and stress. The target compounds will be small molecules that are expected to penetrate the CNS and have reasonable stability so that they will be useful medications and can be used as in vitro and in vivo probes. PUBLIC HEALTH RELEVANCE: Stimulant abuse and addiction continues to be a major societal problem the United States. Mounting evidence suggests that one of the best methods for combating stimulant addiction is the agonist approach in which drugs replace the biochemical deficits caused by chronic stimulant. Such an approach may be the only way to address the wide ranges of symptoms observed during withdrawal as well as the urge to relapse into drug taking behavior. Dual dopamine/serotonin releasers represent one approach to such agonist therapies and will be developed in this research program.