Discovery of potent and selective neuropeptide Y Y2 receptor antagonist probes

发现有效且选择性的神经肽 Y Y2 受体拮抗剂探针

• 批准号: 8058759
• 负责人: Michael Darin Cameron
• 金额: $ 88.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-10 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058759
• 关键词: Affinity; Alcohol dependence; Alcoholism; Alcohols; Biological Assay; Cells; Chemicals; Clinical; Data; Dependence; Development; Disease; Evaluation; Extramural Activities; Goals; Health; In Vitro; Laboratories; Ligands; Medical; National Institute on Alcohol Abuse and Alcoholism; Pharmaceutical Chemistry; Pharmacology; Pharmacotherapy; Play; Process; Program Development; Property; Rattus; Reliance; Research; Role; Self Administration; Site; Societies; Source; Staging; Therapeutic; Therapeutic Agents; Translational Research; United States National Institutes of Health; Validation; Work; addiction; alcohol research; animal efficacy; base; counterscreen; design; drug discovery; efficacy testing; experience; high throughput screening; in vivo; neuropeptide Y; neuropeptide Y2 receptor; novel; pre-clinical; public health relevance; receptor; socioeconomics; tool

DESCRIPTION (provided by applicant): The overall and specific goal of this application is the identification of novel high affinity and selective functional antagonists of the neuropeptide Y Y2 receptor subtype. We aim to identify, design and synthesize novel, potent, and selective Y2R antagonists as tools for research on alcohol dependence with potential as clinically effective therapeutic agents. We aim to achieve this goal via medicinal chemistry design based on existing Y2R ligands that are available or have been obtained in our high throughput screening efforts. The disease target, alcohol addiction and dependence, represents an enormous health burden on society and for which currently available pharmacotherapies have insufficient efficacy. We propose Y2R antagonism as a mechanism to achieve the therapeutic objective. While no clinical validation exists for the mechanism, the hypothesis supported by preclinical data from multiple sources. A translational research team composed of medicinal chemists, computational chemists, cell biologists, pharmacologists, and physiologists with extensive drug discovery experience is prepared to execute a molecule development program centered on the design, synthesis and evaluation of agents for that can be used in alcohol dependence research based on their actions at the NPY Y2 receptor. Compounds will be developed in an iterative cycle of ligand evaluation and re-design. Medicinal chemistry efforts will focus on development of new and better compounds. The in vitro pharmacology of novel compounds will be assessed in multiple cell-based assays and will include NPY receptor counterscreens to routinely determine potency and selectivity at a very early stage. DMPK properties of leads will be determined both in vitro and in vivo throughout the process as well. Additional in vivo assessments of compound activity on alcohol dependence, including a validated test for efficacy assessment in reducing alcohol self-administration in rats, will be performed in the NIH/NIAAA laboratory of Dr. Markus Heilig. All other work will be performed at extramural sites. Unique aspects of our approach include an early reliance upon selectivity data, DMPK information, and early animal efficacy studies. PUBLIC HEALTH RELEVANCE: Alcoholism, an enormous health burden in the USA and worldwide, is one of the most imposing medical and socioeconomic concerns for our society. The Neuropeptide Y Y2 receptor is thought to play a role in alcohol dependence and addiction. Our goal is to generate a novel chemical entity to be used in alcohol research and with the potential of unraveling Y2R contributions to alcoholism.

描述（由申请人提供）：本申请的总体和具体目标是鉴定神经肽yy2受体亚型的新型高亲和力和选择性功能拮抗剂。我们的目标是识别、设计和合成新的、有效的、选择性的Y2R拮抗剂，作为研究酒精依赖的工具，并有可能成为临床有效的治疗药物。我们的目标是通过基于现有的Y2R配体的药物化学设计来实现这一目标，这些配体是可用的或在我们的高通量筛选工作中获得的。疾病的目标是酒精成瘾和依赖，这对社会构成了巨大的健康负担，目前可用的药物疗法对这一负担的疗效不足。我们提出Y2R拮抗是实现治疗目的的一种机制。虽然没有临床验证存在的机制，从多个来源的临床前数据支持的假设。一个由具有丰富药物发现经验的药物化学家、计算化学家、细胞生物学家、药理学家和生理学家组成的转化研究团队准备执行一个分子开发项目，该项目以药物的设计、合成和评估为中心，基于它们对NPY Y2受体的作用，可用于酒精依赖研究。化合物将在配体评价和重新设计的迭代循环中开发。药物化学的工作将集中在开发新的和更好的化合物。新化合物的体外药理学将通过多种基于细胞的试验进行评估，并将包括NPY受体反筛，以在早期阶段常规确定效力和选择性。在整个过程中，铅的DMPK特性将在体外和体内被确定。在NIH/NIAAA Markus Heilig博士的实验室中，将对化合物对酒精依赖的活性进行进一步的体内评估，包括对减少大鼠酒精自我给药的有效性评估的验证测试。所有其他工作将在校外场地进行。我们方法的独特方面包括早期依赖于选择性数据、DMPK信息和早期动物功效研究。