BIOCHEMICAL CHARACTERIZATION OF OPIATE BINDING SITES

阿片结合位点的生化特征

• 批准号: 3207448
• 负责人: GAVRIL W PASTERNAK
• 金额: $ 16.94万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-05-01 至 1986-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207448
• 关键词: analgesics; autoradiography; brain; drug addiction antagonist; drug metabolism; evolution; hydrazines; hydrazones; ligands; molecular site; morphine; naloxone; opiate alkaloid; peptidases; psychopharmacology; radiotracer; respiratory pharmacology; tissue /cell culture

One of the most important concepts to emerge in recent years in opiate research is the possibility of multiple classes of opioid binding sites. Originally proposed as "receptor dualism", this concept was next expanded to account for the different pharmacological syndromes produced by three general classes of opiates (mu, kappa and sigma) and finally the enkephalins (delta). Soon afterwards studies of the binding characteristics of radiolabeled drugs from all these classes yielded results consistent with binding site heterogeneity. We propose to continue our investigations into the biochemical characterization of these postulated binding subtypes and, in addition, to try to correlate various binding sites with pharmacological actions. This correlation is our ultimate goal. Binding sites per se have little relevance unless they can be of use in understanding the pharmacological properties of drugs. We, therefore, plan both in vitro and in vivo approaches to this question. In vitro we will investigate the binding characteristics of a number of radiolabeled drugs from the four major classes (mu, kappa, sigma and delta). Two general techniques will be used. In the first, we will study binding in brain homogenates. The different ligands will be compared pharmacologically and biochemically. Additional studies will look into the developmental appearance of possible receptor subtypes and phylogenetic differences. We also plan to perform autoradiography using the same ligands. Again, we will compare them pharmacologically and biochemically. However, autoradiography permits us to study the regional localization of receptors at a level unobtainable with homogenate studies. This is important. Other laboratories have demonstrated significant differences in the regional localization of mu and delta binding sites. We also plan to look into the actions of a series of long-acting opiate agonists and antagonists both in vitro and in vivo. In vivo our major aims are to investigate analgesia and respiratory depression. We plan to study a number of drugs from the different classes and use these results to correlate their actions with possible binding subtypes. Ultimately, these studies will hopefully lead to a better understanding of pain and its control.

近年来鸦片制剂中出现的最重要的概念之一 研究是多种类阿片结合位点的可能性。 这个概念最初是作为“受体二元论”提出的， 来解释三种药物引起的不同药理学症状 阿片类药物的一般类别（mu，kappa和sigma），最后是 脑啡肽（δ）。 不久之后，研究了 所有这些类别的放射性标记药物的特征 结果与结合位点异质性一致。 我们建议继续 我们对这些生物化学特征的研究 假设的结合亚型，此外，试图将各种 药理作用的结合位点。 这种相关性是我们 终极目标 结合位点本身没有什么意义，除非它们能够 有助于了解药物的药理学特性。 我们， 因此，计划在体外和体内的方法来解决这个问题。 在 体外，我们将研究一些的结合特性， 来自四个主要类别（μ、κ、σ和 delta）。 将使用两种通用技术。 首先，我们将研究 在脑匀浆中结合。 将比较不同的配体 生物学和生物化学。 更多的研究将探讨 可能的受体亚型的发育外观和系统发育 差异 我们还计划使用相同的 配体。 同样，我们将比较它们的生物化学性质。 然而，放射自显影术使我们能够研究局部定位的 受体的水平无法获得匀浆研究。 这是 重要. 其他实验室已经证明， mu和delta结合位点的区域定位。 我们还计划 研究一系列长效阿片激动剂的作用， 拮抗剂在体外和体内。 在体内，我们的主要目标是 研究镇痛和呼吸抑制。 我们计划研究一个 不同类别的药物数量，并使用这些结果 将他们的行为与可能的绑定子类型关联起来。 最终，这些 这些研究将有助于更好地理解疼痛及其 控制