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.

治疗与手术、创伤和许多相关的疼痛 疾病状态是医疗实践的重要组成部分。 吗啡等阿片类药物仍然是最有效的药物 治疗剧烈疼痛并被广泛用于此目的 尽管有许多严重的胃肠道、心血管和 呼吸系统副作用。 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会导致 瘾。 作用于 Delta 阿片类药物最有效的药物 受体是不能进入中枢神经的肽 常规给药途径后的系统。 新的 如果要在临床上有用，就必须制造化合物。 该提案旨在回答“阿片肽能否 对δ受体有选择性的配体分为几组 因其以不同方式结合该受体的能力而区分 方式？”虽然众所周知，这些药物必须结合 阿片受体产生镇痛等作用，显着 它们的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，正如这暗示的那样，有 这些药物与同一受体结合的方式不同， 那么这种差异如何影响他们的行为方式呢？ 药品 通过与特定受体氨基接触而与受体结合 又由 DNA 编码的酸。 我们建议修改 δ阿片受体具有从以下获得的氨基酸序列 其他阿片受体（mu an kappa）取代现有的 δ受体序列。 这种人工受体被称为 嵌合体，它具有药物识别特性 来自双亲受体。 这种大规模 修饰可用于缩小受体的位置范围 药物被束缚。 受体氨基之间的单独接触 药物的酸和官能团可以通过以下方式确定 选择性地改变编码单个氨基酸的DNA序列 酸使用定点诱变技术。 和 这两个工具我们打算 (1) 表明化学定义 阿片类药物组始终使用特定组 用于δ受体结合的氨基酸和（2）使用 这些不同的“识别位点”负责特定的 这些药物的特性。 这些信息可能会带来革命性的变化 新的阿片类药物是如何设计的，因为它定义了这些药物 通过它们如何与δ受体相互作用而不是通过它们的 化学结构。