Benzodiazepine Analogs as Novel Treatments for Catatonia

描述(申请人提供)：紧张症是一种广泛而严重的综合征，以沉默、昏迷、拒绝进食或饮料、姿势和运动不足为特征，在美国和世界各地影响广泛的精神疾病和其他患者。未经治疗或处理不当的紧张症患者会患上一系列疾病，包括压疮、深静脉血栓、肺血栓、尿潴留、感染和吸入性肺炎，这些疾病可导致严重的医疗损害和死亡。现有的治疗紧张症的方法包括劳拉西潘(一种苯二氮类药物)，通常需要大剂量才能产生有效反应，一些患者反应迟钝，慢性紧张症控制不佳。发现一种治疗紧张症的新方法将具有相当大的商业和科学价值。我们的方法是针对小脑中存在的一种孤儿药物受体，该受体优先被劳拉西潘激活。我们建议开展一个结构-活性关系(SAR)计划，以合成和生物学评价专门设计的劳拉西潘衍生物。从这个项目中，我们的具体目标是发现一个或多个苯二氮卓类类似物，在体外显示出所需的孤儿药物受体效力和选择性。在第二阶段，在体外有希望的化合物将在体内进行基因敲除小鼠的测试，以确认它们的作用模式。最好的先导化合物将进一步优化，然后在紧张症动物模型中进行评估。该项目的长期目标是发现一种治疗紧张症的新的、改进的药剂，该药剂可以获得许可并开发以获得最终市场批准。

DESCRIPTION (provided by applicant): Catatonia is a widespread and serious syndrome characterized by mutism, stupor, refusal to eat or drink, posturing, and hypokinesis, and affects a broad range of psychiatric and other patients in the US and worldwide. Untreated or poorly managed catatonic patients suffer from a wide range of ailments including bed sores, deep venous thrombi, pulmonary emboli, urinary retention, infection, and aspiration pneumonia, which can lead to severe medical impairment and death. Existing treatments for catatonia including lorazepam (a benzodiazepine) often require high doses for an effective response, some patients are unresponsive, and chronic catatonia is poorly controlled. Discovery of a new treatment for catatonia would have a considerable commercial and scientific value. Our approach is to target an orphan drug receptor present in the cerebellum that is preferentially activated by lorazepam. We propose to carry out a Structure-Activity Relationship (SAR) program of synthesis and biological evaluation of specifically designed lorazepam derivatives. From this project we specifically aim to discover one or more benzodiazepine analogs showing the desired in vitro orphan drug receptor potency and selectivity. In Phase Two compounds with a promising in vitro profile will be examined in vivo in knockout mice to confirm their mode of action. The best lead compounds will be further optimized and then evaluated in an animal model for catatonia. The long- term goal of this project is to discover a new, improved pharmaceutical agent for treatment of catatonia that can be licensed and developed for ultimate market approval.