Procognitive and Antipsychotic Actions of JWS-USC-75-IX

JWS-USC-75-IX 的认知和抗精神病作用

• 批准号: 7531871
• 负责人: ALVIN V TERRY
• 金额: $ 19.13万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531871
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Address; Adverse effects; Affect; Affinity; Age; Aggressive behavior; Agitation; Alzheimer' s Disease; American; Amphetamines; Animal Behavior; Animal Model; Antipsychotic Agents; Apomorphine; Attention; Attenuated; Behavioral; Behavioral Symptoms; Cardiovascular system; Caregiver Burden; Caregivers; Caring; Class; Cognition Disorders; Cognitive; Cognitive deficits; Condition; Dementia; Developed Countries; Developing Countries; Development; Direct Costs; Dopamine Agonists; Drug Compounding; Drug Delivery Systems; Elderly; Emotional; Experimental Animal Model; Fright; Generations; Goals; Histamine H3 Receptors; Hyperglycemia; Hyperlipidemia; Impaired cognition; In Vitro; Individual; Institutionalization; Intention; Laboratories; Laboratory Research; Left; Link; Longevity; MK801; Macaca mulatta; Medicine; Memantine; Memory; Metabolic; Methods; Modeling; Molecular; Molecular Target; Monkeys; Motor Activity; Muscarinics; N-Methylaspartate; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurologic; Numbers; Patient Agents; Patients; Performance; Pharmaceutical Preparations; Population; Prevalence; Procedures; Process; Property; Psychotic Disorders; Public Health; Purpose; Ranitidine; Rattus; Reaction; Research; Risk; Risk Factors; Rodent; Sampling; Schizophrenia; Series; Short-Term Memory; Stroke; Testing; Therapeutic; Therapeutic Agents; Weight Gain; Work; age related cognitive disorder; aged; analog; base; concept; design; drug development; drug discovery; innovation; nonhuman primate; novel; nutrition; older patient; optimism; prepulse inhibition; programs; receptor; research study; single molecule; sound; therapeutic target; trend

DESCRIPTION (provided by applicant): An unfortunate result of the rapid rise in the geriatric population in developed countries is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that inflicts an enormous emotional and financial toll on patients as well as caregivers. Unfortunately, the currently available therapies for AD are limited by modest efficacy, adverse side effects, and the fact that the very problematic non-cognitive behavioral symptoms (e.g., agitation) of the illness are left untreated. Such behavioral symptoms are thus; often managed clinically by potent antipsychotic drugs, compounds that are known to produce a variety of adverse metabolic and cardiovascular reactions which are particularly problematic in older patients. Accordingly, one long-term goal of our laboratory is to develop more safe and effective therapeutic agents for patients suffering from both the behavioral and cognitive symptoms of dementia. We have identified one especially promising compound in our drug discovery program that has potential to address these challenges. The compound, JWS-USC-75-IX, is a ranitidine analog that has potent acetylcholinesterase inhibitor (AChEI) properties (i.e., an important therapeutic target for memory enhancement) as well as antagonist activity at both muscarinic (M2) acetylcholine and histamine (H3) receptors (i.e., important drug targets for both cognitive enhancement and antipsychotic activity). Thus, the objective of this application is to determine in animal models if JWS-USC-75-IX is a viable prototypical AD therapeutic agent as well as to provide a proof of concept for the usefulness of single molecular entities with multiple therapeutic targets. Our central hypothesis is that as a result of its activity at multiple drug targets, JWS-USC 75-IX will demonstrate cognitive enhancing effects as well as antipsychotic activity in experimental animal models. To achieve the objectives of this application, we propose two specific aims: 1) To determine the procognitive potential of JWS-USC-75-IX in the aged non-human primate; and 2) To determine the antipsychotic potential of JWS-USC-75-IX in rodents. To address these aims, we will evaluate JWS-USC-75-IX in a delayed match to sample (DMTS) task and a distractor version of this method (DMTS-D) in aged monkeys for effects on working memory and attention, respectively. We will determine antipsychotic potential of the compound in rodents in an amphetamine-induced locomotor activity model and a prepulse inhibition procedure. The significance of this project and its relevance to public health is exemplified by the potential of this novel compound to address two major therapeutic challenges (i.e., cognitive deficits and non-cognitive behavioral symptoms) that are associated not only with neurological illnesses such as AD, but also in psychiatric illnesses such as schizophrenia (i.e., conditions that affect millions of people worldwide). PUBLIC HEALTH RELEVANCE Cognitive deficits and non-cognitive behavioral symptoms are two major therapeutic challenges associated with Alzheimer's disease (AD) and psychiatric illnesses such as schizophrenia. We have synthesized a particularly promising compound (the ranitidine analog, JWS-USC-75-IX) that has potent activity in vitro at three important molecular targets for procognitive and antipsychotic activity, thus potentially addressing these therapeutic challenges in a single molecule. The experiments proposed in this application will thus determine (in animal behavior models) the viability of JWS-USC-75-IX as a prototypical AD-therapeutic agent, and will provide a proof of concept for the usefulness of single molecular entities with multiple therapeutic targets.

描述（由申请人提供）：发达国家老年人群迅速增加的不幸结果是与年龄有关的认知障碍（例如阿尔茨海默氏病）（AD）的患病率越来越高。 AD是一种毁灭性的神经退行性疾病，对患者和护理人员造成了巨大的情感和经济损失。不幸的是，当前可用的AD疗法受到适度的功效，不良副作用以及疾病的非常有问题的非认知行为症状（例如躁动）的限制。因此，这种行为症状是；通常在临床上通过有效的抗精神病药来治疗，这些药物已知会产生各种不良代谢和心血管反应，这些反应在老年患者中尤其有问题。因此，我们实验室的一个长期目标是为患有痴呆症的行为和认知症状的患者开发更安全有效的治疗剂。我们已经在我们的药物发现计划中确定了一种特别有前途的化合物，有可能应对这些挑战。化合物JWS-USC-75-IX是一种ranitidine类似物，具有有效的乙酰胆碱酯酶抑制剂（ACHEI）特性（即，记忆增强的重要治疗靶标），以及对肌肉其他（M2）乙酰胆碱（M2）乙酰胆碱（M2）的拮抗作用（H3）的拮抗作用（I. I. I. I. I. I. I. I.抗精神病药）。因此，该应用的目的是在动物模型中确定JWS-USC-75-IX是否是一种可行的原型AD治疗剂，并为具有多个治疗靶标的单个分子实体的实用性提供了概念验证。我们的中心假设是，由于其在多个药物靶标的活性，JWS-USC 75-IX将在实验动物模型中证明认知增强作用以及抗精神病药。为了实现本应用的目标，我们提出了两个具体的目的：1）确定JWS-USC-75-IX在老年非人类灵长类动物中的认知潜力； 2）确定JWS-USC-75-IX在啮齿动物中的抗精神病性潜力。为了解决这些目标，我们将在延迟匹配的样本（DMTS）任务中评估JWS-USC-75-IX，并在老年猴子中评估该方法（DMTS-D）的分散版本，以分别对工作记忆和注意力的影响。我们将确定在苯丙胺诱导的运动活性模型和预硫抑制程序中，化合物在啮齿动物中的抗精神病药。该项目及其与公共卫生相关的意义得到了这种新颖化合物的潜力，可以解决两种主要的治疗挑战（即认知缺陷和非认知行为症状），这些挑战不仅与AD（例如AD）相关，例如AD，例如精神病患者，例如Schizizophrenia（I.E.E.E.）（即影响Millions norky World worly world world worly world world werme worly werme worly world worly world world world world worlywexpers，公共卫生相关性认知缺陷和非认知行为症状是与阿尔茨海默氏病（AD）和精神分裂症等精神病相关的两个主要治疗挑战。我们合成了一种特别有希望的化合物（Ranitidine类似物，JWS-USC-75-IX），该化合物在体外具有有效的活性，这是在三个重要的分子靶标，用于预测和抗精神病药活性，从而有可能解决单个分子中这些治疗性挑战。因此，在本应用中提出的实验将确定（在动物行为模型中）JWS-USC-75-IX作为典型的Ad治疗剂的生存能力，并将为单个分子实体具有多个治疗靶标的有用性提供概念证明。