Benzodiazepine Analogs as Novel Treatments for Catatonia

描述（由申请人提供）：紧张症是一种广泛而严重的综合征，其特征为沉默，麻木，拒绝进食或饮水，姿势和运动不足，在美国和世界范围内影响广泛的精神病学和其他患者。未经治疗或管理不善的紧张性精神分裂症患者患有各种疾病，包括褥疮、深静脉血栓、肺栓塞、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泮（一种苯二氮卓类药物），通常需要高剂量才能有效治疗，一些患者无反应，慢性紧张症控制不佳。发现一种新的治疗紧张症的方法将具有相当大的商业和科学价值。我们的方法是针对存在于小脑中的孤儿药受体，该受体优先被劳拉西泮激活。我们建议对专门设计的劳拉西泮衍生物进行合成和生物学评价的构效关系（SAR）程序。从这个项目中，我们特别致力于发现一种或多种苯二氮卓类药物类似物，显示出所需的体外孤儿药受体效力和选择性。在第二阶段，将在敲除小鼠体内检测具有体外前景的化合物，以确认其作用模式。最佳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价。该项目的长期目标是发现一种新的，改进的药物制剂用于治疗紧张症，可以获得许可和开发最终市场批准。

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. PUBLIC HEALTH RELEVANCE: Catatonia is a serious health problem in the Unites States, and the existing drug treatments are not always effective and have side effects. We are carrying out research to discover and develop a new drug to help these patients. If we are successful, doctors will have another option to help sufferers of catatonia.