Design of New Therapeutic Agents to Treat Schizophrenia

描述(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。患者照顾者的负担是巨大的，美国的医疗费用为每年600亿美元。FDA批准的几乎所有主要抗精神病药物都主要作用于多巴胺和/或5-羟色胺受体功能。不幸的是，这些抗精神病药物会产生严重的副作用，对治疗精神分裂症的阴性症状和认知障碍无效。因此，迫切需要开发治疗方法来缓解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。我们的长期目标是产生GABAA受体的亚基选择性配体的化合物，以确定不同亚基的生物学功能，并开发治疗人类疾病的新疗法。这里的目标是开发非镇静剂，用于治疗精神分裂症的阴性症状和认知障碍，这些精神分裂症的滥用潜力很小或没有滥用潜力(1个GABAA受体亚基的疗效很弱或没有效果)。我们的中心假设是，携带GABAA受体的3、5或配体的选择性调节剂对携带GABAA受体的2、3和5亚单位(2/3/5)具有相同的效果，在这种疾病的动物模型中已被证明可以减轻精神分裂症的阴性症状和认知障碍，这可能是第一个。 治疗这些精神分裂症症状的候选药物。其基本原理是，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申请和临床试验。提出了以下四个具体目标：1)在精神分裂症动物模型中确定选择性GABAA受体调节剂的活性；2)开发高选择性GABAA受体调节剂；3)开发3种高选择性GABAA受体调节剂；4)测定高亚型选择性GABAA受体调节剂的体内活性。在特定目的下，两个先导化合物成功地逆转了MAM大鼠强直性DA传递的增加，提示这两个化合物可能有效地减轻DA介导的精神障碍。此外，精神刺激物的行为敏感性降低，恢复了HPC-传出结构内的节律性，这有望对缓解精神分裂症的认知和阴性症状具有重要意义。此外，这些化合物能够逆转PCP治疗的大鼠PPI模型中精神分裂症的认知症状，但没有诱导麻木的迹象。在特定的目标2和3下，已经建立了合成所建议的化合物的路线，并且在特定的目标下，已经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。该方法是创新的，因为它专注于手性和亚型选择性咪唑苯并二氮类药物(IBZ)的开发和应用，作为精神分裂症的新疗法。这项拟议的工作意义重大，因为它代表了为精神分裂症患者的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。

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.