Efficacy of GABAA a5 receptor inverse agonists in learning impaired rats

GABAA a5 受体反向激动剂对学习障碍大鼠的功效

基本信息

批准号：
7800650
负责人：
Earl Michael Gibbs
金额：
$ 34.38万
依托单位：
PHYSIOGENIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2012-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7800650
关键词：
Adverse drug effect Adverse effects Agitation Agonist Agreement Alprazolam Alzheimer&apos s Disease Amnesia Animals Anxiety Ataxia Attention deficit hyperactivity disorder Behavior Benzodiazepine Receptor Benzodiazepines Biological Availability Blood Brain Budgets Chloride Ion Clinic Clinical Clinical Trials Cognition Cognition Disorders Complex Dahl Hypertensive Rats Data Depressed mood Development Diazepam Disease model Dose Drug Kinetics Enhancers Essential Drugs Evaluation Foundations Grant Guidelines Hippocampus (Brain)Hour In Vitro Injection of therapeutic agent Lead Learning Learning Disorders Letters Licensing Macaca mulatta Marketing Maximum Tolerated Dose Measures Medicine Membrane Memory Disorders Memory impairment Mental Depression Mental disorders Mind Modeling Molecular Monkeys Motor Mus NIH Program Announcements Names Neuraxis Neurodegenerative Disorders Neurons Oocytes Oral Administration Panic Attack Patients Pharmaceutical Preparations Phase Primates Procedures Rat Strains Rattus Reporting Retrieval Rodent Safety Sampling Schizophrenia Scopolamine Screening procedure Sedation procedure Seizures Site Sleeplessness Small Business Innovation Research Grant Sprague-Dawley Rats Technology Testing Therapeutic Time Toxic effect Toxicology United States Universities Wisconsin Xanax analog behavior test commercialization cooking cost design drug development efficacy testing enthalpy improved material transfer agreement medical schools meetings memory recognition methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate morris water maze mouse model nervous system disorder phase 1 study phase 2 study preclinical safety preclinical study public health relevance receptor response sedative success therapeutic target

项目摘要

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.

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、作用更好、更安全的药物来增强认知。在这个 SBIR I 期项目中，PhysioGenix 将确定 PWZ-029 的功效、药代动力学 (PK)、最大耐受剂量和潜在副作用，PWZ-029 是一种苯二氮卓 (BZ) 化合物，可能对治疗学习和记忆障碍患者有用。 BZs被列为世界卫生组织基本药物目录中的核心药物，市场上的安定和Xanax等药物被广泛用于治疗焦虑、惊恐发作、失眠、躁动和癫痫发作。 BZs 可通过调节 GABAA 受体（大脑中最常见的抑制性受体）对中枢神经系统产生抑制（激动剂）或刺激（反向激动剂）作用。然而，副作用在接受 BZ 治疗的患者中很常见，这可能会限制其使用。例如，安定是 GABAA 受体的完全激动剂，但对患者有副作用，包括镇静、健忘症和共济失调。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。由于这些不良副作用可归因于 BZ 与 GABAA 受体复合物不同亚基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 BZ。 GABAA 受体复合物包含 15 个亚基，在海马体中大量表达，因此被认为是治疗认知障碍（如阿尔茨海默病和 ADHD）的治疗靶点。考虑到这一点，PWZ-029 由威斯康星大学密尔沃基分校的 James Cook 博士设计，作为 GABAA 受体的反向激动剂，主要在 15 亚基上具有亚型和功能选择性。最近的卵母细胞体外研究表明，与 11、12 和 13 亚基相比，PWZ-029 对 15 亚基的功能选择性高出 60 倍。行为测试还表明，PWZ-029 具有认知增强能力，从而使其成为可行的治疗候选者。在此，我们将在啮齿类动物和恒河猴中评估 PWZ-029 增强认知的能力。对于啮齿动物研究，口服给药后将在血液和大脑中测量 PWZ-029 的 PK，以评估其生物利用度。最大耐受剂量研究将作为先导优化毒理学的一部分进行，这也可能检测 PWZ-029 是否会引起癫痫发作。 PWZ-029 的促惊厥倾向将使用 PTZ 小鼠模型直接测量。行为测试将纳入具有自然认知缺陷的大鼠品系以及标准的东莨菪碱失忆症模型。最后，恒河猴将用于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 II 期研究，旨在扩大临床前安全性和有效性测试，最终进行临床试验。商业化机会将通过治疗精神健康障碍的药物开发工作来实现。公共健康相关性：在进一步开发药物之前，需要进行临床前研究来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其治疗潜力。随着 PWZ-029 距离临床又近了一步，患有学习障碍和患有神经退行性疾病并发症的患者将大大受益。