Design of New Treatment Agents for Drug Abuse

描述（由申请人提供）：开发治疗药物成瘾障碍的有效药物对社会非常重要。在许多中枢神经系统疾病的治疗方面已经取得了巨大的进步，这些疾病以前是非常衰弱的，基本上是无法治愈的。然而，可卡因成瘾已被证明是极难有效用药的。为了治疗可卡因成瘾，已经作出了广泛的努力来开发单胺再摄取抑制剂形式的长效激动剂。尽管开发了几种有前途的先导化合物，但没有一种在临床中被证明是广泛有效的。因此，越来越清楚的是，潜在的治疗药物在其他生物化学靶点的相互作用需要探索。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，并且由于越来越多的数据记录了DA和5-羟色胺之间的相互作用，改变5-羟色胺神经传递被认为是药物治疗的可行靶点。最近的一系列论文表明，5HT2A受体拮抗剂可能是减轻可卡因行为影响的有希望的治疗靶点。本申请中提出的研究将验证高选择性5HT2A受体拮抗剂或具有选择性5HT2A受体拮抗剂但与单胺转运蛋白有一定亲和力的化合物将有潜力作为治疗可卡因成瘾的治疗剂。这将通过有机合成、药物化学、药理学和行为生理学相结合的多学科研究项目来实现，探索一类新的5HT2A受体拮抗剂的功效。

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.