Efficacy of GABAA a5 receptor inverse agonists in learning impaired rats

描述(由申请人提供)：在美国，患有学习和记忆障碍的患者数量正在迅速增加。这就需要开发新的、效果更好、更安全的药物来增强认知。在这个SBIR第一阶段项目中，PhysioGenix将确定PWZ-029的疗效、药代动力学(PK)、最大耐受量和潜在的副作用。PWZ-029是一种苯二氮卓(BZ)化合物，可能被证明对治疗学习和记忆障碍患者有用。BZS被列为世卫组织基本药物清单中的核心药物，市场上的安定和Xanax等药物被广泛用于治疗焦虑、恐慌症发作、失眠、躁动和癫痫发作。BZS可通过调节大脑中最普遍的抑制性受体GABAA受体，对中枢神经系统产生抑制(激动剂)或刺激(反向激动剂)效应。然而，在接受BZS治疗的患者中，副作用很常见，这可能会限制其使用。例如，安定是GABAA受体的完整激动剂，但在患者中有副作用，包括镇静、健忘和共济失调。非选择性BZ反向激动剂，如DMCM，通常会引起焦虑，并可能导致动物癫痫发作。由于这些不受欢迎的副作用可归因于BZS与GABAA受体复合体不同亚单位的非特异性相互作用，因此正在开发仅保留所需药理反应的功能特异性BZS。包含15个亚基的GABAA受体复合体在海马区大量表达，因此被认为是治疗阿尔茨海默氏症和ADHD等认知障碍的治疗靶点。考虑到这一点，威斯康星大学密尔沃基分校的詹姆斯·库克博士设计了PWZ-029，作为GABAA受体的反向激动剂，其亚型和功能选择性主要位于15亚基。最近在卵母细胞上的体外研究表明，PWZ-029对15个亚基的功能选择性比11、12和13高60倍。行为测试也表明PWZ-029具有增强认知的能力，从而使其成为可行的候选治疗药物。在这里，PWZ-029增强认知的能力将在啮齿类动物和恒河猴身上进行评估。在啮齿动物研究中，PWZ-029的PK将在口服后在血液和脑中进行测量，以评估其生物利用度。最大耐受剂量研究将作为铅优化毒理学的一部分进行，这也可能检测PWZ-029是否会导致癫痫发作。我们将使用PTZ小鼠模型直接测量PWZ-029的致惊厥倾向。行为学测试将包括具有天然认知缺陷的大鼠品系以及标准的东莨菪碱健忘症模型。最后，猕猴将被用来测量潜在的镇静副作用，并确认PWZ-02增强认知能力的初步数据。成功将导致第二阶段研究，旨在扩大临床前安全性和有效性测试，最终导致临床试验。商业化机会将通过治疗精神健康障碍的药物开发努力实现。 公共卫生相关性：在进一步的药物开发之前，需要进行临床前研究，以确定功能选择性苯二氮卓类化合物(如PWZ-029)的生物利用度和安全性。筛选具有相关疾病模型的化合物将有助于评估它们的治疗潜力。随着PWZ-029向临床又迈进了一步，学习障碍患者和那些因神经退行性疾病而遭受并发症的患者将大大受益。

DESCRIPTION (provided by applicant): The number of patients in the United States afflicted with learning and memory disorders is rapidly increasing. This necessitates the development of new, better acting and safer medications for enhancing cognition. In this SBIR Phase I project, PhysioGenix will determine the efficacy, pharmacokinetics (PK), maximum tolerated dose and potential side-effects of PWZ-029, a benzodiazepine (BZ) compound that may prove useful for treating patients with learning and memory disorders. BZs are listed as a Core Medicine in the WHO Essential Drug List and those on the market, such as Valium and Xanax, are widely used for the treatment of anxiety, panic attacks, insomnia, agitation and seizures. BZs can cause depressing (agonist) or stimulating (inverse agonist) effects on the central nervous system by modulating the GABAA receptor, the most prevalent inhibitory receptor within the brain. However, side-effects are common in patients treated with BZs and this can limit their use. For example, Valium is a full agonist of the GABAA receptor but has a side-effect profile in patients that includes sedation, amnesia and ataxia. Nonselective BZ inverse agonists, like DMCM, are often anxiogenic and can cause seizures in animals. Because these unwanted side-effects can be attributed to nonspecific interactions of the BZs for different subunits of the GABAA receptor complex, functionally specific BZs that retain only the desired pharmacological response are being developed. GABAA receptor complexes that contain 15 subunits are abundantly expressed in the hippocampus and therefore considered to be a therapeutic target for treating cognitive disorders, like Alzheimer's and ADHD. With this in mind, PWZ-029 was designed by Dr. James Cook of the University of Wisconsin-Milwaukee, to be an inverse agonist for the GABAA receptor having subtype and functional selectivity predominantly at the 15 subunit. Recent in vitro studies in oocytes have shown that PWZ-029 has up to 60-fold more functional selectivity for the 15 subunit compared to 11, 12 and 13. Behavior tests also suggest that PWZ-029 has cognition enhancing capabilities, thereby making it a feasible therapeutic candidate. Here, the ability of PWZ-029 to enhance cognition will be assessed in both rodents and rhesus monkeys. For rodent studies, the PK of PWZ-029 will be measured in blood and brain following oral administration to assess its bioavailability. Maximum tolerated dose studies will be carried out as part of lead optimization toxicology, which may also detect if PWZ-029 will cause seizures. The proconvulsant liability of PWZ-029 will be measured directly using the PTZ mouse model. The behavior tests will incorporate rat strains that have natural deficits in cognition along with a standard scopolamine amnesia model. Finally, rhesus monkey will be used to measure potential sedative side-effects along with confirming preliminary data for the ability of PWZ-02 to enhance cognition. Success will lead to Phase II studies that will aim to expand preclinical safety and efficacy testing ultimately leading to clinical trials. Commercialization opportunities will be realized via drug development efforts for treating mental health disorders. PUBLIC HEALTH RELEVANCE: Preclinical studies that determine the bioavailability and safety of functionally selective benzodiazepine compounds, like PWZ-029, are required prior to further drug development. Screening of compounds with relevant disease models will help to assess their therapeutic potential. Patients with learning disorders and those suffering from complications due to neurodegenerative diseases will greatly benefit as PWZ-029 moves another step closer to the clinic.