POTENTIAL TREATMENT MEDICATIONS FOR DRUG ABUSE

该应用程序的主要目标是发现和开发治疗药物滥用的药物。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和安非他明成瘾和戒断的生化和分子机制。临床证据表明，厌食治疗PHEN/FEN，联合释放剂芬特明（DA释放剂）和芬氟拉明（5-羟色胺释放剂）减少可卡因依赖；本应用程序的主要目的是发现和开发新的类双释放模拟联合治疗。本研究的范围将包括：(1)基于已知释放物的几个小分子文库的合成，同时合成其他潜在的小苯胺支架；(2)利用高通量释放试验对化合物进行体外评价；(3)建立选择性释放物活性的理论模型；(4)动物模型体内评价。可卡因奖励的“多巴胺假说”推动了目前许多成瘾研究，但它未能找到能使药物。最近的一些证据表明，奖励机制可能以比以前认为的更大的方式涉及5-羟色胺。因此，可卡因奖励的“双重赤字”模型是该项目的基础。显示DA和5-羟色胺释放活性的化合物，而不是NE，将测试NE的摄取。候选药物还将评估5-HT2A、MAO-A和MAO-B的体外活性。符合我们体外标准的化合物将在体内进行神经毒性测试，并通过体内微透析确认其释放特性。我们还将向NIDA可卡因治疗发现项目提交有趣的候选药物，以进一步进行体外和体内评估。

The major goal of this application is to discover and develop medications for the treatment of substance abuse. 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. Clinical evidence indicates that the anorectic therapy PHEN/FEN, a combination of releasers phentermine (DA releaser) and fenfluramine (5-HT releaser) decreases cocaine dependence; the primary objective of this application is to discover and develop novel classes of dual releasers which mimic the combination therapy. The scope of this study will include: (1) the synthesis of several small molecule libraries based on known releasers concurrent with the synthesis other potential small phenylamine scaffolds; (2) in vitro evaluation of the compounds using a high throughput releaser assay; (3) the development of a theoretical model for selective releaser activity; and (4) in vivo evaluation in animal models. The "dopamine hypothesis" of cocaine reward which drives much of current addiction research has failed to find DAergic medications. Some recent evidence suggests that the reward mechanism may involve 5-HT in a much larger way than previously thought. A "dual deficit" model for cocaine reward is thus the basis for the project. Compounds that demonstrate DA and 5-HT releasing activity, but not NE, will be tested for NE uptake. Candidates will also be evaluated for 5-HT2A, MAO-A, and MAO-B in vitro activity. Compounds which fit our in vitro criteria will be tested in vivo for neurotoxicity and their releasing properties confirmed via in vivo microdialysis. We will also submit interesting candidates to the NIDA Cocaine Treatment Discovery Program for further in vitro and in vivo evaluation.