Design of New Treatment Agents for Drug Abuse

新型药物滥用治疗剂的设计

• 批准号: 7894883
• 负责人: HUW M DAVIES
• 金额: $ 37.95万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894883
• 关键词: Affinity; Agonist; Attenuated; Behavioral; Binding; Biochemical; Biological Assay; Central Nervous System Diseases; Clinic; Cocaine; Cocaine Dependence; Data; Development; Disease; Dopamine; Drug Addiction; Drug abuse; HTR2A gene; Housing; In Vitro; Interdisciplinary Study; Lead; Measurement; Monkeys; National Institute of Drug Abuse; Organic Synthesis; Paper; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Pilot Projects; Self Administration; Series; Serotonin; Serotonin Receptor 5-HT2A; Societies; Structure; System; Testing; Therapeutic Agents; addiction; analog; base; behavioral pharmacology; design; enantiomer; in vivo; inhibitor/antagonist; monoamine; neurotransmission; novel; programs; receptor; reuptake; therapeutic target

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.

描述（由申请人提供）：开发治疗药物成瘾疾病的有效药物对社会具有重要意义。许多中枢神经系统疾病的治疗已经取得了巨大进展，这些疾病以前使人严重衰弱且基本上无法治愈。然而，可卡因成瘾已被证明极难通过药物治疗取得良好效果。人们付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，用于治疗可卡因成瘾。尽管开发了几种有前途的先导化合物，但没有一种被证明在临床上广泛有效。因此，越来越清楚的是，需要探索与其他生化靶标相互作用的潜在治疗剂。由于可卡因是多巴胺 (DA) 和血清素 (5-HT) 系统的间接激动剂，并且随着记录 DA 和 5-HT 之间相互作用的数据不断增加，改变 5-HT 神经传递已被认为是药物治疗的可行目标。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检验以下假设：高度选择性5HT2A受体拮抗剂或具有选择性5HT2A受体拮抗作用但还对单胺转运蛋白具有一定亲和力的化合物将具有作为治疗可卡因成瘾的治疗剂的潜力。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，探索一类新型 5HT2A 受体拮抗剂的功效。