Novel Serotonin Reuptake Inhibitors for Autism Treatment

用于治疗自闭症的新型血清素再摄取抑制剂

• 批准号: 6754670
• 负责人: Kevin G. Pinney
• 金额: $ 17.23万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-23 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754670
• 关键词: antipsychotic agents; autism; chemical information system; chemical structure function; combinatorial chemistry; drug design /synthesis /production; drug screening /evaluation; human tissue; inhibitor /antagonist; laboratory rat; mass spectrometry; mental disorder chemotherapy; neurotransmitter transport; nuclear magnetic resonance spectroscopy; psychopharmacology; receptor binding; serotonin inhibitor; serotonin receptor; serotonin transporter

DESCRIPTION (provided by applicant): Clinical evidence has shown that selective serotonin reuptake inhibitors (SSRIs) and "atypical" antipsychotics are drugs commonly used and proven effective for the treatment of some of the most important and incapacitating symptoms associated with autism spectrum disorders. SSRIs have been identified by researchers and patients' families as some of the most clinically useful agents, especially in targeting repetitive preoccupations, perseverative behaviors and anxiety-related symptoms. Atypical antipsychotics have also proven effective for improving other types of symptoms such as hyperactivity, and in reducing the frequency and intensity of temper outbursts and aggression in patients with autism. Nevertheless, these currently available drugs still face an undesired side effect profile that limits their use, especially in treating young children. The proposed research program focuses on the synthesis and biological evaluation of novel bi-functional molecules that, by incorporating into one molecular entity the biological effects of both SSRIs and atypical antipsychotics, can provide synergism in terms of their potential efficacy over a wider variety of the core symptoms in patients with autism. In order to develop the proposed bi-functional molecules, we have designed and plan to prepare a series of new drug candidates, which judiciously combine portions of SSRIs with known 5-HT2A receptor antagonists. This is a pilot research study, which represents an innovative approach to the pharmacological treatment of autism. It can be extremely beneficial since it has the strong potential to overcome the drawbacks of two separate pharmacological treatments, which include high costs and undesired side effects. Biological evaluation of the proposed molecules will provide valuable information about the structural features necessary to achieve strong and highly selective binding to both target sites, and give preliminary evidence in regard to whether the new molecules represent valuable "lead" compounds for further in vitro and in vivo investigations. Finally, we believe that this study supports the mission of NIH in its ongoing search for effective treatments for autistic disorder as well as for depressive illnesses, and that the results obtained by this research, will further advance our understanding of autism and lead to improved treatment methods.

描述(由申请人提供)：临床证据表明，选择性5-羟色胺再摄取抑制剂(SSRI)和“非典型”抗精神病药物是常用的药物，已被证明对治疗与自闭症谱系障碍有关的一些最重要和使人丧失能力的症状有效。SSRIs已被研究人员和患者家属确定为一些最有临床实用价值的药物，特别是在针对重复的关注点、持之以恒的行为和焦虑相关症状方面。非典型抗精神病药物也被证明对改善其他类型的症状有效，如多动，并在减少自闭症患者脾气爆发和攻击的频率和强度方面。然而，这些目前可用的药物仍然面临着不受欢迎的副作用，限制了它们的使用，特别是在治疗幼儿方面。拟议的研究计划侧重于新型双功能分子的合成和生物学评估，通过将SSRIs和非典型抗精神病药物的生物学效应合并为一个分子实体，可以在自闭症患者的更广泛的核心症状方面提供潜在疗效方面的协同作用。为了开发所提出的双功能分子，我们已经设计并计划制备一系列新的候选药物，它们明智地将部分SSRI与已知的5-HT2A受体拮抗剂结合起来。这是一项先导性研究，代表了自闭症药物治疗的一种创新方法。这可能是非常有益的，因为它有很大的潜力克服两种单独的药物治疗的缺点，包括高昂的成本和不希望看到的副作用。对所提议的分子的生物学评价将提供关于实现与两个靶点的强和高选择性结合所需的结构特征的有价值的信息，并为新分子是否代表有价值的体外和体内研究的“先导”化合物提供初步证据。最后，我们相信，这项研究支持了美国国立卫生研究院为自闭症和抑郁性疾病寻找有效治疗方法的使命，这项研究的结果将进一步加深我们对自闭症的理解，并导致改进治疗方法。