Design of New Therapeutic Agents to Treat Schizophrenia

治疗精神分裂症的新治疗药物的设计

• 批准号: 8642208
• 负责人: James M Cook
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 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/8642208
• 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

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，美国的护理费用每年超过 600 亿美元。事实上，FDA 批准的所有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，这些抗精神病药物会产生严重的副作用，并且对于治疗精神分裂症的阴性症状和认知缺陷无效。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缺陷，最好是使用新的候选药物。我们的长期目标是生成GABAA受体的β亚基选择性配体化合物，以确定不同β亚基的生物学功能并开发人类疾病的新疗法。这里的目标是产生非镇静剂，用于治疗精神分裂症的阴性症状和认知缺陷，并且很少或没有滥用潜力（对 1 GABAA 受体亚基的功效较弱或没有）。我们的中心假设是，选择性调节剂“3”、“5”或对带有 GABAA 受体的“2”、“3”和“5 亚基”(“2/”3/“5”) 具有同等功效的配体，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，可能是第一个治疗这种疾病的药物。 解决精神分裂症这些症状的候选药物。理由是，一旦本申请中描述的当前 lea 化合物的开发成功完成，这些候选药物将可用于 IND 备案和临床试验。提出以下四个具体目标： 1）确定选择性 GABAA 受体调节剂在精神分裂症动物模型中的活性； 2) 开发高选择性GABAA受体调节剂¡5和¡2/¡3/¡5； 3）开发高度选择性的3种GABAA受体调节剂； 4) 确定高度亚型选择性 GABAA 受体调节剂的体内活性。在特定目标下，两种先导化合物成功逆转了 MAM 大鼠中强直性 DA 传递的增加，这表明这些化合物可有效缓解 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 HPC 传出结构内的节律性，预计这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，已经建立了生成所提出化合物的合成路线，并且在具体目标 4 下，已在包括恒河猴在内的不同动物模型中评估了先导化合物的非镇静特性。该方法具有创新性，因为它专注于手性和亚型选择性咪唑并苯二氮卓类药物（IBZ）作为精神分裂症新疗法的开发和应用。这项拟议的工作意义重大，因为它代表了针对精神分裂症患者认知功能受损和阴性症状开发第一种疗法的连续研究的第一步。