Design of New Treatment Agents for Drug Abuse

描述(申请人提供)：开发治疗药物成瘾障碍的有效药物对社会具有重要意义。在治疗许多中枢神经系统疾病方面取得了很大进展，这些疾病以前非常虚弱，基本上无法治愈。然而，事实证明，用药物治疗可卡因成瘾非常困难，效果很好。为开发治疗可卡因成瘾的单胺再摄取抑制剂形式的长效激动剂，已经做出了广泛的努力。尽管已经开发了几种有希望的先导化合物，但没有一种在临床上被证明是广泛有效的。因此，需要探索潜在的治疗药物与其他生化靶点的相互作用。由于可卡因是多巴胺(DA)和5-羟色胺(5-HT)系统的间接激动剂，而且随着越来越多的数据证明DA和5-羟色胺(5-HT)之间的相互作用，改变5-羟色胺的神经传递被认为是药物治疗的可行靶点。最近的一系列文献表明，5HT2A受体拮抗剂可能是减轻可卡因行为影响的有前途的治疗靶点。本申请中提出的研究将检验这样一种假设，即高选择性的5HT2A受体拮抗剂或具有选择性5HT2A受体拮抗剂但也与单胺转运体有一定亲和力的化合物将有可能作为治疗可卡因成瘾的药物。这将通过一个结合有机合成、药物化学、药理学和行为生理学的多学科研究计划来实现，探索一类新的5HT2A受体拮抗剂的疗效。

DESCRIPTION (provided by applicant): The development of effective medications for the treatment of drug addiction disorders is of great importance to society. Great advances have been made in the treatment of many CNS diseases that were previously highly debilitating and essentially incurable. Cocaine addiction, however, has proven to be extremely difficult to medicate with good effect. An extensive effort has been made to develop long-acting agonists in the form of monoamine reuptake inhibitors for the treatment of cocaine addiction. Even though several promising lead compounds were developed none have proven to be broadly effective in the clinic. Thus, it is becoming clear that potential therapeutic agents interacting at other biochemical targets need to be explored. Because cocaine is an indirect agonist at dopamine (DA) and serotonin (5-HT) systems, and as a result of growing data documenting interactions between DA and 5-HT, altering 5-HT neurotransmission has been considered a viable target for pharmacotherapies. A series of recent papers have demonstrated that 5HT2A receptor antagonists may be promising therapeutic targets for attenuating the behavioral effects of cocaine. The studies proposed in this application will test the hypothesis that either highly selective 5HT2A receptor antagonists or compounds with selective 5HT2A receptor antagonism but also with some affinity to monoamine transporters will have potential as therapeutic agents for the treatment of cocaine addiction. This will be achieved through a multidisciplinary research program combining organic synthesis, medicinal chemistry, pharmacology and behavioral physiology, exploring the efficacy of a new class of 5HT2A receptor antagonists.