Novel Serotonin Reuptake Inhibitors for Autism Treatment

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（SSRIs）和“非典型”抗精神病药是常用药物，并被证明可有效治疗与自闭症谱系障碍相关的一些最重要和致残性症状。SSRIs已被研究人员和患者家属确定为临床上最有用的药物之一，特别是在针对重复性专注，持续行为和焦虑相关症状方面。非典型抗精神病药物也被证明有效改善其他类型的症状，如多动症，并减少自闭症患者脾气爆发和攻击的频率和强度。然而，这些目前可用的药物仍然面临着不希望的副作用，这限制了它们的使用，特别是在治疗幼儿中。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价，通过将SSRIs和非典型抗精神病药物的生物学作用纳入一个分子实体，可以在其潜在疗效方面提供协同作用。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，其明智地将SSRI的联合收割机部分与已知的5-HT 2A受体拮抗剂结合。这是一项试点研究，代表了自闭症药物治疗的创新方法。它可以是非常有益的，因为它具有克服两种单独的药物治疗的缺点的强大潜力，这些缺点包括高成本和不希望的副作用。生物学评价提出的分子将提供有价值的信息，必要的结构特征，以实现强大的和高度选择性的结合到两个目标网站，并提供初步证据，关于新的分子是否代表有价值的“铅”化合物，进一步在体外和体内的调查。最后，我们相信这项研究支持了NIH的使命，即继续寻找自闭症和抑郁症的有效治疗方法，并且这项研究所获得的结果将进一步促进我们对自闭症的理解，并改进治疗方法。

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.