Design of New Therapeutic Agents to Treat Schizophrenia

治疗精神分裂症的新治疗药物的设计

基本信息

批准号：
8500922
负责人：
James M Cook
金额：
$ 38.39万
依托单位：
UNIVERSITY OF WISCONSIN MILWAUKEE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8500922
关键词：
Address Adverse effects Affect Affinity Animal Disease Models Animal Model Animals Antipsychotic Agents Attention Attenuated Behavioral Biological Process Brain Caregivers Caring Catalepsy Chemical Structure Clinical Trials Cognitive Cognitive deficits Complex Delusions Development Disease Dopamine Dopamine Receptor Evaluation Family Family Caregiver Functional disorder Goals Hallucinations Healthcare Human Impaired cognition Impairment Knowledge Lead Ligands Macaca mulatta Mediating Memory Mental disorders Mission Modeling Molecular Probes Motivation Motor Neuraxis Neurobehavioral Manifestations Outcome Patients Periodicity Pharmaceutical Preparations Physiological Processes Population Property Psychotic Disorders Public Health Quality of life Rattus Research Route Schizophrenia Sensory Societies Structure Symptoms Therapeutic Agents Work analog atypical antipsychotic base cognitive function cost design drug candidate effective therapy enantiomer human disease improved in vivo innovation novel novel therapeutics psychologic psychosocial psychostimulant public health relevance receptor receptor function serotonin receptor social success transmission process

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating disorder that affects almost 1% of the world's population. The burden on the caregivers of patients is immense, and the cost of care in the U.S. is >$60 billion/y. Virtually all of the major antipsychotics approved y the FDA act primarily on dopamine and/or serotonin receptor function. Unfortunately, these antipsychotics produce serious side effects and are ineffective in treating negative symptoms and cognitive deficits of schizophrenia. Thus, there is an urgent need to develop treatments to alleviate these symptoms and deficits for schizophrenia patients preferably with novel drug candidates. Our long term goal is to generate compounds that are -subunit selective ligands of the GABAA receptors to determine the biological functions of different -subunits and to develop new therapies for human diseases. The objective here is to generate nonsedating agents for the treatment of negative symptoms and cognitive deficits of schizophrenia with little or no abuse potential (weak or no efficacy at 1 GABAA receptor subunits). Our central hypothesis is that selective modulators of the ¿3,¿5, or ligands with equal efficacy for the ¿2,¿3, and ¿5 subunits (¿2/¿3/¿5) bearing GABAA receptors, which have been shown to attenuate negative symptoms and cognitive deficits of schizophrenia in animal models of this disease, are potentially the first drug candidates to address these symptoms of schizophrenia. The rationale is that these drug candidates will be available for IND filing and clinical trials once the development of current lea compounds described in this application is successfully completed. The following four specific aims are proposed: 1) Determine the activity of selective GABAA receptor modulators in animal models of schizophrenia; 2) Develop highly ¿5 and ¿2/¿3/¿5 selective GABAA receptor modulators; 3) Develop highly 3 selective GABAA receptor modulators; and 4) Determine in vivo activity of highly subtype selective GABAA receptor modulators. Under specific aim one two lead compounds successfully re- versed the increase of tonic DA transmission in MAM rats, which suggests that these compounds would be effective in alleviating DA-mediated psychosis. Additionally, behavioral sensitivity to psychostimulants was reduced, restoring the rhythmicity within HPC-efferent structure, which is expected to be important for the alleviation of cognitive and negative symptoms of schizophrenia. Additionally, these compounds were able to reverse the cognitive symptoms of schizophrenia in the PPI model of PCP treated rats but induced no signs of catalepsy. Under specific aims 2 and 3, synthetic routes to generate the proposed compounds are already establish and under specific aims 4 nonsedating properties of lead compounds has been evaluated in different animal models including rhesus monkeys. The approach is innovative because it focuses on the development and application of chiral and -subtype selective imidazobenzodiazepines (IBZ) as new therapies for schizophrenia. The proposed work is significant because it represents the first step in a continuum of research to develop the first therapies for impaired cognitive function and negative symptoms of schizophrenia patients.

描述（由申请人提供）：精神分裂症是一种使人衰弱的疾病，影响着世界上近 1% 的人口，患者护理人员的负担是巨大的，美国每年的护理费用几乎超过 600 亿美元。 FDA 批准的主要抗精神病药主要作用于多巴胺和/或血清素受体功能，不幸的是，这些抗精神病药会产生严重的副作用，并且对治疗阴性无效。因此，迫切需要开发治疗方法来减轻精神分裂症患者的这些症状和认知缺陷，最好是使用新的候选药物。确定不同β亚基的生物学功能并开发针对人类疾病的新疗法。本发明的目的是产生非镇静剂，用于治疗精神分裂症的阴性症状和认知缺陷，且几乎不产生任何副作用。没有滥用潜力（对 1 个 GABAA 受体亚基效力较弱或没有）。我们的中心假设是 ¿ 的选择性调节剂。 3,¿ 5，或具有同等功效的配体 ¿ 2,¿ 3、和??带有 GABAA 受体的 5 个亚基 (¿2/¿3/¿5) 已被证明可以减轻精神分裂症动物模型中的阴性症状和认知缺陷，这可能是第一个其理由是，一旦成功完成本申请中描述的现有 lea 化合物的开发，这些候选药物将可用于 IND 备案和临床试验。提出了以下四个具体目标。确定精神分裂症动物模型中选择性 GABAA 受体调节剂的活性；2) 高度发展 ¿ 5 和 ¿ 2/¿ 3/¿ 5 种选择性 GABAA 受体调节剂；3) 开发 3 种高选择性 GABAA 受体调节剂；以及 4) 在特定目标下，确定两种先导化合物成功逆转 MAM 中强直 DA 传递的增加。大鼠，这表明这些化合物可以有效缓解 DA 介导的精神病，此外，对精神兴奋剂的行为敏感性降低，恢复体内的节律性。 HPC 高效结构预计对于缓解精神分裂症的认知和阴性症状非常重要。此外，这些化合物能够逆转 PCP 治疗大鼠 PPI 模型中的精神分裂症认知症状，但不会引起僵住症状。在具体目标 2 和 3 下，生成所提出的化合物的合成路线已经建立，并且在具体目标 4 下，先导化合物的非镇静特性已在包括恒河猴在内的不同动物模型中进行了评估。该方法具有创新性，因为它专注于开发和应用手性和亚型选择性咪唑并苯二氮卓类药物（IBZ）作为精神分裂症的新疗法。这项工作意义重大，因为它代表了开发第一种针对精神分裂症的疗法的连续研究的第一步。精神分裂症患者的认知功能和阴性症状。