Discovery of potent and selective neuropeptide Y Y2 receptor antagonist probes

说明书(申请人提供)：本申请的总体和具体目标是鉴定神经肽Y Y2受体亚型的新型高亲和力和选择性功能拮抗剂。我们的目标是发现、设计和合成新的、有效的和选择性的Y2R拮抗剂，作为研究酒精依赖的工具，具有潜在的临床有效治疗药物的潜力。我们的目标是通过基于现有Y2R配体的药物化学设计来实现这一目标，这些配体是我们高通量筛选工作中可用的或已经获得的。疾病的目标是酒精成瘾和依赖，这给社会带来了巨大的健康负担，目前可用的药物疗法对这些疾病的疗效不足。我们建议将Y2R拮抗作为实现治疗目标的机制。虽然目前还没有关于这一机制的临床验证，但该假说得到了来自多个来源的临床前数据的支持。一个由药物化学家、计算化学家、细胞生物学家、药理学家和具有丰富药物发现经验的生理学家组成的转化研究小组准备执行一个分子开发计划，该计划的中心是设计、合成和评估可用于酒精依赖研究的药物，其基础是它们在NPY Y2受体上的作用。化合物将在配体评估和重新设计的迭代周期中开发。药物化学的努力将集中在开发新的和更好的化合物上。新化合物的体外药理学将通过多个基于细胞的分析进行评估，并将包括NPY受体反筛选，以便在非常早期的阶段常规确定效力和选择性。在整个过程中，铅的DMPK属性也将在体外和体内进行测定。对化合物对酒精依赖的体内活性的其他评估，包括对减少大鼠酒精自我给药的有效性评估的验证测试，将在Markus Heilig博士的NIH/NIAAA实验室进行。所有其他工作将在校外地点进行。我们方法的独特方面包括早期依赖选择性数据、DMPK信息和早期动物疗效研究。

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.