MICA: Valium without the sedation: Non-sedating anxiolytic GABAA receptor modulators for the treatment of anxiety disorders.

该提案旨在开发非镇静性抗焦虑药物（“无镇静的安定”），这将代表50多年来焦虑障碍治疗的第一个重大进展。焦虑症是患者去看全科医生的最常见原因，其中，广泛性焦虑症（GAD）最为普遍。大约5%的人在一生中的某个时期受到影响，其特征是持续、普遍和过度的担忧。因此，这是一种使人衰弱的疾病，对社会的影响相当于抑郁症，每年给英国造成100亿英镑的损失。由于各种原因，目前对广泛性焦虑症的治疗并不令人满意，而且自20世纪60年代初苯二氮卓类药物被引入以来，还没有重大的创新。苯二氮卓类药物是一种所谓的轻微镇静剂，其中最著名的是安定（安定，又名“母亲的小帮手”）。苯二氮卓类药物在减少焦虑方面是有效的（也就是说，它们是抗焦虑药），但镇静是一个主要的副作用。直到最近，所有试图确定下一代药物“拨出”这些副作用，特别是镇静，都没有成功。然而，随着我们对苯二氮卓类药物如何起作用的知识的最新进展，我们现在能够了解开发非镇静性抗焦虑药所需的条件，更重要的是，我们如何识别此类药物。这项提案旨在利用我们在知识方面的这些突破。苯二氮卓类药物通过改变大脑中一种叫做γ -氨基丁酸（GABA）的化学物质（神经递质）的作用而起作用。这种神经递质与大脑中四种类似的蛋白质结合，分别是alpha1、alpha2、alpha3和alpha5 GABAA受体（GABAAR）。最近的数据表明，alpha1亚型负责镇静，因此，假设通过特异性影响alpha2和alpha3（“抗焦虑”）GABAAR亚型，而避免alpha1（“镇静”）亚型，应该有可能确定一种非镇静的抗焦虑化合物。这一假设被证明是正确的，许多动物实验表明，GABAAR alpha2/alpha3药物确实是一种非镇静性抗焦虑药，早期的人类研究也支持这一假设。由于一些与其作用机制无关的原因，以前在人体中测试的GABAAR alpha2/alpha3药物不再被开发，因此我们希望继续研究这一领域，并开发新的GABAAR alpha2/alpha3药物，这些药物有可能彻底改变焦虑症的治疗，特别是广泛性焦虑症。

This proposal aims to develop non-sedating anxiolytic drugs ("Valium without the sedation") that will represent the first major advance in the treatment of anxiety disorders for over 50 years. Anxiety disorders are the most common cause of patients visiting their GP and of these, generalized anxiety disorder (GAD) is the most prevalent. It affects around 5% of the population at some time in their life and is characterized by persistent, pervasive and excessive worrying. Consequently, it is a debilitating disorder that has an impact on society that is equivalent to depression and costs the UK in the region of £10 billion a year. Current treatments for GAD are unsatisfactory for various reasons and there have been no major innovations since benzodiazepines were introduced in the early 1960s. Benzodiazepines are a class of so-called minor tranquilizer drugs the most famous of which is diazepam (Valium, aka "Mother's Little Helper"). Benzodiazepines are effective at reducing anxiety (i.e., they are anxiolytics) but sedation is a major side-effect. Until recently, all attempts to identify next-generation drugs that "dial-out" these side-effects, particularly the sedation, have been unsuccessful. However, following recent advances in our knowledge of how benzodiazepines work, we are now in a position to understand what is required to develop a non-sedating anxiolytic and, more importantly, how we can identify such drugs. It is these breakthroughs in our knowledge that this proposal aims to exploit. Benzodiazepines act by altering the effects of a chemical in the brain (neurotransmitter) called gamma-aminobutyric acid (GABA). This neurotransmitter bind to four similar proteins in the brain called alpha1, alpha2, alpha3 and alpha5 GABAA receptors (GABAAR). Recent data suggests that the alpha1 subtype is responsible for sedation and consequently, it is hypothesised that by specifically affecting the alpha2 and alpha3 (the "anxiolytic") GABAAR subtypes while avoiding the alpha1 (the "sedation") subtype, it should be possible to identify an anxiolytic compound which is non-sedating. This hypothesis turns out to be correct with many experiments in animals showing that a GABAAR alpha2/alpha3 drug is indeed a non-sedating anxiolytic and early studies in man also support this hypothesis. Previous GABAAR alpha2/alpha3 drugs that were tested in man are no longer being developed due to a number of reasons unrelated to their mechanism of action and we therefore wish to continue with this area of research and develop novel GABAAR alpha2/alpha3 drugs that have the potential to revolutionize the treatment of anxiety disorders in general and GAD in particular.