Development of Potential Treatment Medications for Drug Abuse

摘要 该申请的主要目标是发现和开发用于治疗物质依赖性疾病的药物。 虐待此外，我们预计开发的化合物也将作为生物化学探针， 更好地了解可卡因和安非他明的生物化学和分子机制 成瘾和戒断。本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。迄今为止，大多数针对“激动剂”疗法的努力， 兴奋剂成瘾的研究集中在发现选择性DA摄取阻滞剂上。然而，增加 有证据表明，可能需要双重DA/5-HT选择性或非选择性化合物来“纠正” 戒断期间刺激诱导的缺陷的总体。实验结果发表以来， Grant申请还建议释放剂作为一类可以是有效的突触激动剂治疗。的 这三种神经递质系统之间的最佳活性平衡尚不清楚;然而， DA能活性必须与其它活性某种组合一起存在。因此， 这项申请是为了进一步发展双DA/5 HT和非选择性“通用”激光引线， 在项目初期。这些化合物也可用于治疗其它精神疾病 比如抑郁焦虑和压力目标化合物将是小分子， 渗透CNS并具有合理的稳定性，使得它们将是有用的药物，并可用于 体外和体内探针。

ABSTRACT 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.