Benzodiazepine Analogs as Novel Treatments for Catatonia

苯二氮卓类似物作为紧张症的新型治疗方法

• 批准号: 8196257
• 负责人: HOWARD P SARD
• 金额: $ 35万
• 依托单位: ORGANIX, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196257
• 关键词: ABCB1 gene; Achievement; Active Sites; Acute; Adverse effects; Affect; Agonist; Animal Model; Anti-Anxiety Agents; Anticonvulsants; Aspiration Pneumonia; Autoimmune Diseases; Benzodiazepine Receptor; Benzodiazepines; Biological; Bipolar Disorder; Butyric Acids; Catatonia; Cell Nucleus; Cerebellum; Cessation of life; Chronic; Clinical; Collaborations; Computer Assisted; Decubitus ulcer; Development; Docking; Dose; Drug Receptors; Eating; Electroconvulsive Shock; Embolism; Encephalitis; Evaluation; Exhibits; GPR68 gene; Gated Ion Channel; Goals; Grant; Health; Human; Impairment; In Vitro; Infection; Inpatients; Intellectual Property; Knockout Mice; Lead; Legal patent; Licensing; Ligands; Lorazepam; Lung; Marketing; Mediating; Medical; Modification; Molecular; Muscle relaxants; Mutism; National Institute of Mental Health; North Carolina; Orphan Drugs; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Posture; Preclinical Drug Evaluation; Psychotropic Drugs; Recording of previous events; Research; Resources; Schizophrenia; Sedation procedure; Serotonin Agonists; Site; Small Business Innovation Research Grant; Stroke; Structure; Structure-Activity Relationship; Stupor; Syndrome; Testing; Thrombus; United States; Universities; Urinary Retention; Venous; Work; analog; base; design; drinking; drug development; functional group; human GPR68 protein; human GPRC5C protein; improved; in vivo; interest; neuropsychiatry; novel; programs; receptor; respiratory; response

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.

描述（由申请人提供）：Catatonia是一种普遍且严重的综合症，其特征是Mutism，昏昏欲睡，拒绝饮食，姿势和发药性，并影响了美国和世界各地的各种精神病学和其他患者。未经治疗或管理不善的约定患者患有广泛的疾病，包括床疮，深静脉血栓，肺栓塞，尿位retention留，感染和吸入性肺炎，这会导致严重的医疗障碍和死亡。包括劳拉西m（苯二氮卓）在内的卡塔托尼症的现有治疗方法通常需要高剂量才能有效反应，有些患者没有反应，并且慢性卡托尼亚受到控制不良。发现卡塔尼氏症的新疗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孤儿药物受体，该药物受到Lorazepam的优先激活。我们建议对特定设计的Lorazepam衍生物进行合成和生物学评估的结构活性关系（SAR）计划。从这个项目中，我们特别旨在发现一个或多个苯二氮卓类似物，显示所需的体外孤儿药物受体效力和选择性。在第二阶段的化合物中，将在敲除小鼠中在体内检查具有有希望的体外剖面的化合物，以确认其作用方式。最好的铅化合物将进一步优化，然后在Catatonia动物模型中进行评估。该项目的长期目标是发现一种新的，改进的药物治疗Catatonia的药物，可以获得许可和开发以获得最终的市场认可。 公共卫生相关性：卡塔托尼亚在联合州是一个严重的健康问题，现有的药物治疗并不总是有效的，并且具有副作用。我们正在进行研究以发现和开发一种新药来帮助这些患者。如果我们成功，医生将有另一种选择来帮助卡塔托尼亚的患者。