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：
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
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/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

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（由申请人证明）：精神分裂症是一种衰弱的疾病，几乎是全球人口的1％。 Y FDA主要是在精神分裂症的症状和精神分裂症的认知缺陷中促进了严重的副作用。确定不同subunits的生物学功能，并在这里开发新的疗法假设是。 3，� 5，或具有同等疗效的配体2，� 3和„ 5个亚基（2/€3/¿ 这些精神分裂症的症状）高度发展5和» 2/ 3/¿ 5选择性的GABAA受体调整器YPE选择性GABAA回收剂。精神分裂症。包括恒河猴的使用。