Indolobenzox- and Thiazepines as Atypical Antipsychotic Agents

吲哚苯氧和硫氮卓类药物作为非典型抗精神病药

• 批准号: 7539253
• 负责人: Parthasarathi Rajagopalan
• 金额: $ 17.57万
• 依托单位: DAYA DRUG DISCOVERIES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-02 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539253
• 关键词: Indolobenzox; Thiazepines; Atypical; Antipsychotic; Agents

DESCRIPTION (provided by applicant): Schizophrenia is a frightening and heart-rending malady which affects about 15 out of 10,000 persons annually in the United States and is characterized by a group of disorders that produces severe disturbances in cognition, reality testing, mood, interpersonal relations, social and work function. Schizophrenia affects men and women equally and the symptoms associated with this dreadful disorder can largely be divided into the positive and the negative categories. The negative symptoms consist of behavioral deficits such as blunting of emotions, language deficits, and lack of energy while the positive symptoms include auditory and visual hallucinations, delusions, and bizarre behavior. The critical roles that the neurotransmitters dopamine and serotonin play in the disease is becoming increasingly clear with the isolation and cloning of the five receptors for the former and fourteen for the latter. Drugs currently used in the treatment of schizophrenics, which are known as neuroleptics or antipsychotics, are designed to relieve the diverse symptoms of the disease so that the patient can function as close to a normal human being as possible and also to delay or prevent possible relapse. Conventional or `classical' antipsychotics such as chlorpromazine (Thorazine) and haloperidol (Haldol). while are quite effective in relieving the positive symptoms of schizophrenia, are beset not only with undesirable albeit reversible side effects such as restlessness, stiffness, and tremor but also with a more serious one as tardive dyskinesia which is not fully reversible. With the advent of the newer and so-called `atypical antipsychotics' such as clozapine (Clozaril), olanzapine (Zyprexa), and aripiprazole (Abilify), the side effects associated with the classical antipsychotics have been alleviated to a large extent. These drugs, in contrast to the `classical' antipsychotics, are highly effective in relieving both the positive and the negative symptoms of schizophrenia and elicit their response by blocking both the dopamine D2 as well as the serotonin 5-HT2A receptors in the pertinent regions of the brain. However these drugs produce different types of side effects such as sometimes fatal agranulocytosis (clozapine) and significant but undesirable weight gain (olanzapine). Therefore, there is a tremendous need for new and potent antpsychotics with drastically reduced or even void of the deleterious side effects mentioned above and this grant proposal describes the synthesis and biological evaluation of novel atypical antipsychotics of the types A and B shown below. R N N Type A: X = O; Type B: X = S X Schizophrenia is an insidious and frightening malady which affects about 15 out of 10,000 persons annually in the United States and is characterized by a group of disorders that produces diverse disturbances in cognition, reality testing, mood, interpersonal relations, social and work function. PUBLIC HEALTH RELEVANCE Schizophrenia affects men and women equally and the symptoms associated with this dreadful disorder can largely be divided into the positive and the negative categories. The negative symptoms consist of behavioral deficits such as blunting of emotions, language deficits, and lack of energy while the positive symptoms include auditory and visual hallucinations, delusions, and bizarre behavior. Conventional or `classical' antipsychotics such as chlorpromazine (Thorazine) and haloperidol (Haldol). while are quite effective in relieving the positive symptoms of schizophrenia, are beset not only with undesirable albeit reversible side effects such as restlessness, stiffness, tremor, and tardive dyskinesia. With the advent of the newer and so-called `atypical antipsychotics', such as clozapine (Clozaril) and olanzapine (Zyprexa), and aripiprazole (Abilify), the side effects associated with the classical antipsychotics have been alleviated to a large extent. However these drugs produce different types of side effects such as sometimes fatal agranulocytosis (clozapine) and significant but undesirable weight gain (olanzapine). Therefore, there is a great need for new and potent antpsychotics with drastically reduced or even void of the deleterious side effects mentioned above, and this grant proposal focuses on the development of such new atypical antipsychotics.

描述(申请人提供)：精神分裂症是一种可怕和令人心碎的疾病，每年在美国每10,000人中约有15人受到影响，其特征是一组在认知、现实测试、情绪、人际关系、社交和工作功能方面产生严重障碍的疾病。精神分裂症对男性和女性的影响是一样的，与这种可怕的疾病相关的症状基本上可以分为积极和消极两类。消极症状包括行为缺陷，如情感迟钝、语言障碍和缺乏活力，而积极症状包括听觉和视觉幻觉、妄想和奇怪的行为。随着5种多巴胺受体和14种5-羟色胺受体的分离和克隆，神经递质多巴胺和5-羟色胺在疾病中的关键作用日益明显。目前用于治疗精神分裂症的药物被称为神经抗精神病药或抗精神病药物，旨在缓解疾病的各种症状，使患者能够尽可能接近正常人的功能，并延缓或防止可能的复发。常规或“经典”抗精神病药物，如氯丙嗪(托拉津)和氟哌啶醇(氟哌啶)。虽然在缓解精神分裂症的阳性症状方面相当有效，但不仅受到烦躁、僵硬和震颤等可逆的不良副作用的困扰，而且还有一种更严重的副作用，如迟发性运动障碍，这是不完全可逆的。随着较新的所谓非典型抗精神病药物的出现，如氯氮平(Clozaril)、奥氮平(Zyprexa)和阿立哌唑(Abilify)，与经典抗精神病药物相关的副作用在很大程度上得到了缓解。与经典的抗精神病药物相比，这些药物在缓解精神分裂症的阳性和阴性症状方面都非常有效，并通过阻断大脑相关区域的多巴胺D2和5-羟色胺5-HT2a受体来引起它们的反应。然而，这些药物产生不同类型的副作用，如有时致命的粒细胞缺乏症(氯氮平)和显着但不受欢迎的体重增加(奥氮平)。因此，迫切需要新的、有效的抗精神病药物，同时大大减少或甚至消除上述有害副作用，本赠款提案描述了如下所示的A和B类新型非典型抗精神病药物的合成和生物学评价。R N N A型：X=O；B型：X=S X精神分裂症是一种隐匿而可怕的疾病，每年在美国每10,000人中约有15人受到影响，其特征是一组障碍，在认知、现实测试、情绪、人际关系、社会和工作功能方面产生不同的障碍。与公共卫生有关的精神分裂症对男性和女性的影响均等，与这种可怕的疾病相关的症状基本上可以分为积极和消极两类。消极症状包括行为缺陷，如情感迟钝、语言障碍和缺乏活力，而积极症状包括听觉和视觉幻觉、妄想和奇怪的行为。常规或“经典”抗精神病药物，如氯丙嗪(托拉津)和氟哌啶醇(氟哌啶)。虽然在缓解精神分裂症的阳性症状方面非常有效，但不仅受到烦躁、僵硬、震颤和迟发性运动障碍等不良但可逆的副作用的困扰。随着较新的所谓非典型抗精神病药物的出现，如氯氮平(Clozaril)、奥氮平(Zyprexa)和阿立哌唑(Abilify)的出现，与经典抗精神病药物相关的副作用在很大程度上得到了缓解。然而，这些药物产生不同类型的副作用，如有时致命的粒细胞缺乏症(氯氮平)和显着但不受欢迎的体重增加(奥氮平)。因此，迫切需要新的、有效的抗精神病药物，这些药物的副作用大大减少，甚至没有上述有害副作用，而这项拨款提案侧重于开发这种新的非典型抗精神病药物。