Design of New Therapeutic Agents to Treat Schizophrenia

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，美国的护理费用为每年600亿美元。事实上，FDA批准的所有主要抗精神病药物主要作用于多巴胺和/或血清素受体功能。不幸的是，这些抗精神病药物产生严重的副作用，对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-亚基选择性配体化合物，以确定不同-亚基的生物学功能，并开发人类疾病的新疗法。本研究的目的是研制用于治疗精神分裂症阴性症状和认知缺陷的非镇静药物，这些药物很少或没有滥用的可能性（对1 GABAA受体亚单位的疗效较弱或无疗效）。我们的中心假设是，对携带GABAA受体的¿2、¿3和¿5亚基（¿2/¿3/¿5）具有同等功效的¿3、¿5或配体的选择性调节剂可能是第一种，这种调节剂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

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.