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，我们期望所开发的化合物也将作为生化探针，有助于更好地了解可卡因和安非他明成瘾和戒断的生化和分子机制。本提案的最初目标是设计、合成和评估多巴胺（DA）、血清素（5-HT）和去甲肾上腺素（NE）释放剂。迄今为止，大多数对兴奋剂成瘾的“激动剂”治疗的努力都集中在选择性DA摄取阻断剂的发现上。然而，越来越多的证据表明，可能需要双DA/5-HT选择性或非选择性化合物来“纠正”戒断期间兴奋剂引起的全部缺陷。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。这三种神经递质系统活动的最佳平衡尚不清楚；然而，它假定能活动必须与其他活动的某种组合一起存在。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“通用”释放导联。这些化合物也可能对治疗其他精神疾病如抑郁症有用。目标化合物将是有望穿透中枢神经系统并具有合理稳定性的小分子，因此它们将成为有用的药物，并可用作体外和体内探针。

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 nonselective "universal" releaser leads generated during the initial project period. These compounds may also be useful for treating other psychiatric disorders such as depression. 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.