POTENTIAL TREATMENT MEDICATIONS FOR DRUG ABUSE

该应用程序的主要目标是发现和开发用于治疗药物滥用的药物。 开发的化合物也将作为生物化学探针，有助于更好地了解可卡因和安非他明成瘾和戒断的生物化学和分子机制。临床证据表明，厌食治疗PHEN/FEN，释放剂芬特明（DA释放剂）和芬氟拉明（5-HT释放剂）的组合降低可卡因依赖性;本申请的主要目的是发现和开发新型的双重释放剂，其模拟组合治疗。 本研究的范围将包括：（1）基于已知释放剂的几种小分子文库的合成，同时合成其他潜在的小苯胺支架;（2）使用高通量荧光素酶测定法对化合物进行体外评价;（3）开发选择性荧光素酶活性的理论模型;以及（4）在动物模型中进行体内评价。可卡因奖赏的“多巴胺假说”推动了当前成瘾研究的大部分，但未能找到DA能药物。 最近的一些证据表明，奖励机制可能涉及5-HT在一个更大的方式比以前认为的。 因此，可卡因奖励的“双重赤字”模型是该项目的基础。 将测试表现出DA和5-HT释放活性而非NE释放活性的化合物的NE摄取。还将评价候选物的5-HT 2A、MAO-A和MAO-B体外活性。 将在体内测试符合我们体外标准的化合物的神经毒性，并通过体内微透析确认其释放特性。 我们还将提交感兴趣的候选人到NIDA CONDITION治疗发现计划进行进一步的体外和体内评估。

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.