GPCRs: Chemical-Scale Studies with Unnatural Amino Acids

GPCR：非天然氨基酸的化学规模研究

基本信息

批准号：
7796863
负责人：
DENNIS A DOUGHERTY
金额：
$ 30.4万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7796863
关键词：
Acetylcholine Address Agonist Amino Acids Aromatic Amino Acids Aspartate Attention deficit hyperactivity disorder Basic Science Behavior Binding Binding Sites Biogenic Amine Receptors Biogenic Amines Cations Chemicals Chemistry Cholinergic Receptors Data Development Dopamine Dopamine Receptor Drug Industry Drug Receptors Electrophysiology (science)Esters Family G-Protein-Coupled Receptors Gated Ion Channel Generic Drugs Goals Grant Human Hydrogen Bonding Hydrophobic Interactions Image Ion Channel Ions Knowledge Laboratories Ligands Medicine Methodology Methods Mind Modeling Molecular Biology Muscarinic Acetylcholine Receptor Oocytes Organic Chemistry Parkinson Disease Pharmaceutical Preparations Pharmacologic Substance Play Proline Proteins Research Role Rotation Schizophrenia Sensory Receptors Site Specificity Structure System Testing Time Translating Vertebral column Work analog dopamine D4 receptor experience fluorophore functional group human CHRM4 protein human DRD4 protein insight interest member nervous system disorder preference premature prevent public health relevance receptor receptor coupling receptor function research study tool tryptophyltyrosine

项目摘要

DESCRIPTION (provided by applicant): Roughly 40% of human medicines target G protein-coupled receptors (GPCRs), and ongoing research throughout the pharmaceutical industry is focused on these ubiquitous proteins. There are hundreds of different GPCRs, and despite considerable efforts, our knowledge of their structures and modes of action is limited. Over the past decade, our laboratory has developed a powerful methodology for revealing drug- receptor interactions. The method combines organic chemistry, molecular biology, and electrophysiology to incorporate unnatural amino acids into receptors. We have applied the approach to many neuroreceptors and ion channels, with informative and important results. In the present work we propose to apply the unnatural amino acid methodology to the study of GPCRs. Our initial target will be a family of dopamine receptors, which are implicated in treatments for a number of neurological disorders including Parkinson's disease and schizophrenia. The insights gained from this work will be of great value to efforts to develop safer, more efficacious pharmaceuticals that target dopamine receptors in particular, and GPCRs in general. PUBLIC HEALTH RELEVANCE Efforts to develop safer, more efficacious pharmaceuticals are greatly aided by insights into precisely how drugs interact with their target receptors. The present work will provide just such information for the most ubiquitous targets of the pharmaceutical industry. The results will aid in the development of new treatments for Parkinson's disease, schizophrenia, and attention-deficit hyperactivity disorder.

描述（由申请人提供）：大约40％的人类药物靶向G蛋白偶联受体（GPCR），整个制药行业的持续研究都集中在这些无处不在的蛋白质上。有数百种不同的GPCR，尽管做出了巨大的努力，但我们对它们的结构和行动方式的了解仍然有限。在过去的十年中，我们的实验室开发了一种强大的方法来揭示药物受体相互作用。该方法结合了有机化学，分子生物学和电生理学，将非天然氨基酸掺入受体中。我们已经将方法应用于许多神经受体和离子渠道，并具有丰富的重要结果。在目前的工作中，我们建议将非天然氨基酸方法应用于GPCR的研究。我们的最初目标是多巴胺受体家族，与包括帕金森氏病和精神分裂症在内的多种神经系统疾病的治疗有关。从这项工作中获得的见解对于开发尤其是针对多巴胺受体的更安全，更有效的药物（通常是GPCR）的努力将具有很大的价值。公共卫生相关性为开发更安全，更有效的药物的努力得到了对药物如何与目标受体相互作用的见解，从而极大地帮助了他们。目前的工作将为制药行业的最普遍目标提供此类信息。结果将有助于开发帕金森氏病，精神分裂症和注意力缺陷多动障碍的新疗法。