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: 9034672
• 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/9034672
• 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; Health; 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 therapeutics; psychologic; psychosocial; psychostimulant; receptor; receptor function; reduce symptoms; 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（由适用提供）：精神分裂症是一种使人衰弱的疾病，影响了世界人口的近1％。对患者的照顾者的烧伤是巨大的，美国的护理费用> 600亿美元/y。实际上，所有主要的抗精神病药都批准了FDA主要作用于多巴胺和/或5-羟色胺受体功能。不幸的是，这些抗精神病药会产生严重的副作用，并且无法治疗精神分裂症的负面症状和认知缺陷。这是迫切需要开发治疗方法来减轻这些症状的方法，并为精神分裂症患者定义，最好用新型的候选药物来定义。我们的长期目标是生成GABAA受体的sububunit选择性配体的化合物，以确定不同 - 亚基的生物学功能，并开发针对人类疾病的新疗法。这里的目的是产生非义务药物来治疗精神分裂症的负面症状和认知缺陷，而滥用潜力很少或没有滥用潜力（1 GABAA受体亚基时弱或没有效率）。我们的核心假设是，€3，€5或配体的选择性调节剂具有相同效率的„ 2，€3和5个亚基（2/€3/€5）的轴承GABAA接收器，这些接收器已证明可以减弱这种疾病的负面症状和认知性缺陷。 候选药物来解决精神分裂症的这些症状。理由是，一旦成功完成了本应用中描述的当前LEA化合物的开发，这些候选药物将用于IND提交和临床试验。提出了以下四个特定目的：1）确定精神分裂动物模型中选择性GABAA受体调节剂的活性； 2）高度开发5和»2/»3/€5选择性GABAA受体调节剂； 3）发展高度3个选择性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。在特定的目标下，一两个铅化合物成功地重新体现了MAM大鼠中强调DA传播的增加，这表明这些化合物将有效减轻DA介导的精神病。此外，对精神刺激剂的行为敏感性减少了，从而恢复了HPC效率结构内的节奏性，这对于缓解精神分裂症的认知和负面症状至关重要。此外，这些化合物能够逆转PPI治疗的大鼠PPI模型中精神分裂症的认知症状，但没有引起细胞蛋白的迹象。在特定的目标2和3下，已经建立了生成所提出化合物的合成途径，并且在特定的目标下，已在包括恒河猴在内的不同动物模型中评估了铅化合物的非含量特性。这种方法具有创新性，因为它专注于手性和-subtype选择性咪达唑苯二氮卓（IBZ）作为精神分裂症的新疗法。提出的工作很重要，因为它代表了一项连续研究的第一步，以开发精神分裂症患者的认知功能受损和负面症状的第一个疗法。