BIOCHEMICAL CHARACTERIZATION OF OPIOID LIGANDS AND RECEPTORS

阿片类配体和受体的生化特征

• 批准号: 6300719
• 负责人: HENRY I YAMAMURA
• 金额: $ 10.45万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300719
• 关键词: CHO cells; analgesics; biological signal transduction; chimeric proteins; drug design /synthesis /production; endogenous opioid; enkephalins; ligands; neuropeptides; opioid receptor; peptide analog; peptide chemical synthesis; receptor binding; receptor expression; receptor sensitivity; site directed mutagenesis; stimulant /agonist; synthetic peptide

The treatment of pain associated with surgery, trauma and many diseases states is an essential part of medical practice. Opinoids such as morphine remain the most effective drugs for the treatment of severe pain and are widely used for this purpose despite haveing many serious gastrointestinal, cardiovascular and respiratory side effects. Worst still, these drugs produce a state of physical dependence after repeated use that can lead to addiction. The most effective drugs acting at delta opioid receptors are peptides that cannot enter the central nervous system after conventional routes of administration. New compounds must be made if they are to be useful in the clinic. This proposal seeks to answer the questin, "Can opioid peptide ligands selective for the delta receptor be divided into groups distinguished by their ability to bind this receptor in different ways?" While it is well understood that these drugs must bind opioid receptors to produce effects such as analgesia, marked differences in their chemical structures strongly suggest that they must do so in different ways. If, as this implies, there are different ways for these drugs to bind to the same receptor, then how does this difference affect the way they act? Drugs bind to receptors through contacts with specific receptor amino acids that are in turn encoded by DNA. We propose to modify delta opioid receptors to have amino acid sequences obtained from other opioid receptors (mu an kappa) substituted for existing delta receptor sequences. Such an artificial receptor is called a chimera and it would have drug recognition properties derived from both parent receptors. This kind of large scale modification can be used to narrow down where in the receptor drugs are bound. Individual contacts between receptor amino acids and functional groups of a drug can be determined by selectively changing the DNA sequence encoding a single amino acid using the technique of site-directed mutagenesis. With these two tools we intend to (1) show that chemically defined groups of opioid drugs consistently use particular groups of aiminoacids for delta receptor binding and (2) that the use of these different "recognition sites" is responsible for specific properties of these drugs. This information could revolutionize how new opioid drugs are designed since it defines these drugs by how they interact with delta receptors rather than by their chemical structures.

与手术，创伤和许多相关的疼痛治疗 疾病状态是医学实践的重要组成部分。 诸如吗啡之类的观点仍然是最有效的药物 治疗剧烈疼痛，并广泛用于此目的 尽管有许多严重的胃肠道，心血管和 呼吸副作用。 最糟糕的是，这些药物会产生 重复使用后的身体依赖状态可能导致 瘾。 作用于三角洲阿片类药物的最有效的药物 受体是无法进入中枢神经的肽 常规管理途径后的系统。 新的 如果化合物在诊所中有用，则必须制作。 该提议试图回答Questin，“阿片类肽可以 配体选择性的增量受体分为组 以它们在不同的方式结合该受体的能力而区别 方式吗？ 阿片类药物受体产生诸如镇痛等作用，标记 其化学结构的差异强烈表明 他们必须以不同的方式这样做。 如果正如这所暗示的那样， 这些药物与同一受体结合是不同的方式， 那么，这种差异如何影响他们的行动方式？ 毒品 通过与特定受体氨基的接触与受体结合 酸反过来由DNA编码。 我们建议修改 达美阿片受体具有从中获得的氨基酸序列 其他阿片类药物受体（MU A KAPPA）代替现有 增量受体序列。 这样的人造受体称为 嵌合体并具有衍生的药物识别特性 来自两个父受体。 这种大规模 修改可用于缩小受体中的位置 药物是约束的。 受体氨基之间的个别接触 药物的酸和功能组可以通过 有选择地更改编码单个氨基的DNA序列 使用位置定向诱变技术的酸。 和 我们打算（1）这两个工具表明化学定义 一组阿片类药物始终使用特定组 Delta受体结合的AIMINOACIDS和（2）使用 这些不同的“识别站点”负责特定 这些药物的特性。 这些信息可能会彻底改变 由于它定义了这些药物，因此如何设计新阿片类药物 通过他们如何与三角洲受体互动而不是通过他们的 化学结构。