Indolobenzox- and Thiazepines as Atypical Antipsychotic Agents

描述（由申请人提供）：精神分裂症是一种令人恐惧和心碎的疾病，每年在美国约有1万人中有15人患有这种疾病，其特征是一组疾病，在认知、现实测试、情绪、人际关系、社会和工作功能方面产生严重干扰。精神分裂症对男性和女性的影响相同，与这种可怕疾病相关的症状在很大程度上可分为阳性和阴性两类。阴性症状包括情绪迟钝、语言障碍、精力不足等行为缺陷，阳性症状包括视听幻觉、妄想、怪异行为。神经递质多巴胺和血清素在疾病中发挥的关键作用随着前者的5个受体和后者的14个受体的分离和克隆而变得越来越清楚。目前用于治疗精神分裂症的药物被称为抗精神病药或抗精神病药，其设计目的是减轻这种疾病的各种症状，使患者的功能尽可能接近正常人，并延缓或防止可能的复发。传统或“经典”抗精神病药物，如氯丙嗪（Thorazine）和氟哌啶醇（Haldol）。虽然它们在缓解精神分裂症的阳性症状方面非常有效，但它们不仅有不受欢迎的副作用，如烦躁不安、僵硬和震颤，而且还有更严重的迟发性运动障碍，这是不完全可逆的。随着氯氮平（Clozaril）、奥氮平（Zyprexa）和阿立哌唑（Abilify）等新型“非典型抗精神病药物”的出现，与经典抗精神病药物相关的副作用已在很大程度上得到缓解。与“经典”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和血清素5-HT2A受体来引发他们的反应。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）和显著但不受欢迎的体重增加（奥氮平）。因此，对新型有效的抗精神病药物的需求是巨大的，这些药物可以大大减少甚至消除上述有害副作用，本拨款提案描述了如下所示的a和B型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 = 0；精神分裂症是一种潜伏而可怕的疾病，每年在美国每10000人中就有15人患有这种疾病，其特征是一系列疾病，在认知、现实测试、情绪、人际关系、社会和工作功能方面产生各种干扰。精神分裂症对男性和女性的影响相同，与这种可怕疾病相关的症状在很大程度上可分为阳性和阴性两类。阴性症状包括情绪迟钝、语言障碍、精力不足等行为缺陷，阳性症状包括视听幻觉、妄想、怪异行为。传统或“经典”抗精神病药物，如氯丙嗪（Thorazine）和氟哌啶醇（Haldol）。虽然它们在缓解精神分裂症的阳性症状方面非常有效，但它们不仅存在不良的副作用，如烦躁不安、僵硬、震颤和迟发性运动障碍。随着新型和所谓的“非典型抗精神病药物”的出现，如氯氮平（Clozaril）和奥氮平（再普乐）以及阿立哌唑（Abilify），与经典抗精神病药物相关的副作用已在很大程度上得到缓解。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）和显著但不受欢迎的体重增加（奥氮平）。因此，迫切需要一种新型的有效的抗精神病药物，这种药物可以大大减少甚至消除上述有害的副作用，本资助提案的重点是开发这种新的非典型抗精神病药物。

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.