BIOCHEMICAL CHARACTERIZATION OF OPIATE BINDING SITES

阿片结合位点的生化特征

• 批准号: 3207444
• 负责人: GAVRIL W PASTERNAK
• 金额: $ 16.65万
• 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 1989-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207444
• 关键词: affinity labeling; alkylating agents; analgesics; autoradiography; brain mapping; chemical binding; computer data analysis; drug addiction antagonist; drug metabolism; evolution; experimental brain lesion; gel electrophoresis; molecular site; morphine; naloxone; occipital lobe /cortex; opiate alkaloid; psychopharmacology; radiotracer; spinal cord mapping; spinal cord surgery; tissue /cell culture

One of the most important concepts to emerge in recent years in opiate research is the concept of multiple opiate receptors. Originally proposed as "Receptor Dualism", this concept has now been expanded to a whole variety of pharmacologically-defined receptor classes, including mu, delta, kappa, sigman and epsilon. Most recently, two subtypes of mu receptors have been proposed. One, the mu2 site, corresponds to the morphine-selective mu receptor previously characterized. The other, the mu1 site, represents a site first recognized in homogenate binding studies which binds both opiates and opioid peptides with similar very high affinities. The selective mu1 antagonists naloxonazine and naloxazone have proven very helpful in defining the pharmacological role of mu1 sites, implicating them in supraspinal analgesia, for example, but not in respiratory depression or most signs of physical dependence. This application proposes three major aims. The first consists of the characterization of the various classes of opiate binding sites. It consists of the development of selective binding assays for mu1, mu2, delta and kappa sites, followed by their biochemical and pharmacological characterization. The second aim involves the localization of these binding sites using digital subtraction computerized autoradiography. These studies will attempt to localize mu1, mu2, delta and kappa sites using a sophisticated computer analysis to regions within the brain as well as their pre- versus post-synaptic distributions. The last major aim involves continuation of studies on the characterization of a number of irreversible opiates. These compounds will be characterized in binding studies and their selectivity correlated with their pharmacological actions. Selected compounds will be utilized as affinity labels for the receptor. Ultimately, studies such as these should lead to the development to a better understanding of the actions of opiates and their more effective use in the management of pain.

近年来鸦片制剂中出现的最重要的概念之一 研究是多种阿片受体的概念。 最初提出 作为“接受者二元论”，这一概念现在已经扩展到一个整体， 多种药理学定义的受体类别，包括μ，δ， Kappa，Sigman，and P. 最近，两种mu受体亚型 已提出 一个是mu2位点，对应于 吗啡选择性μ受体先前表征。 另一方面 μ 1位点，代表在匀浆结合研究中首次识别的位点 其以类似的非常高的亲和力结合阿片类物质和阿片肽， 亲和力 选择性μ 1拮抗剂纳洛嗪和纳洛宗具有 被证明对确定μ 1位点的药理学作用非常有帮助， 暗示他们在脊髓上镇痛，例如，但不是在 呼吸抑制或大多数身体依赖的迹象。 这 申请书提出了三个主要目标。 第一部分包括 各种类型的阿片类药物结合位点的表征。 它 包括开发针对μ 1、μ 2、δ 和kappa位点，然后是它们的生物化学和药理学 特征化 第二个目标涉及这些本地化 使用数字减影计算机化放射自显影术测定结合位点。 这些研究将试图定位mu1，mu2，delta和kappa位点 利用复杂的计算机分析大脑中的区域， 突触前和突触后的分布。 最后一个主要目标 涉及继续研究一些 不可逆的鸦片 这些化合物的特征在于结合 研究及其选择性与其药理学 行动 选择的化合物将用作用于本发明的化合物的亲和标记。 受体的 最终，像这样的研究应该会导致 为了更好地了解阿片类药物的作用， 有效地用于疼痛的管理。