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用于治疗药物滥用的药物。此外，我们期望开发的化合物也将作为生物化学探针，用于更好地了解可卡因和苯丙胺成瘾和戒断的生物化学和分子机制。本计划的初步目标是设计、合成和评价多巴胺（DA）、5-羟色胺（5-HT）和去甲肾上腺素（NE）释放剂。迄今为止，大多数努力对兴奋剂成瘾的“激动剂”治疗集中在选择性DA摄取阻滞剂的发现。然而，越来越多的证据表明，双DA/5-HT选择性或非选择性的化合物可能需要“纠正”的整体兴奋剂诱导的缺陷在撤退。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之间的最佳活性平衡尚不清楚;然而，假设DA能活性必须与其他活性的某种组合存在。因此，本申请的主要目的是进一步开发在初始项目期间产生的双DA/5 HT和非选择性“通用”激光引线。这些化合物也可用于治疗其他精神疾病，如抑郁症、焦虑症和压力。目标化合物将是小分子，其预期渗透CNS并具有合理的稳定性，使得它们将是有用的药物并可用作体外和体内探针。 公共卫生相关性：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佳方法之一是激动剂方法，即药物取代慢性兴奋剂引起的生化缺陷。这种方法可能是解决戒断期间观察到的各种症状以及重新陷入吸毒行为的冲动的唯一方法。双重多巴胺/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.