BIOCHEMICAL CHARACTERIZATION OF OPIATE BINDING SITES

近年来出现的最重要的概念之一 阿片类药物研究是多个阿片受体的概念。 这一概念最初是作为“受体二元论”提出的，现在已经 已扩展到包括各种药理学定义的 受体类。最近的研究提出了两种亚型的MU 感受器。MU2部位对经典吗啡的反应- 选择性Mu受体在外周的特征 在生物检测和大脑中。MUL受体首先被识别出来 在受体结合研究中具有独特的选择性，发现 大多数，但不是全部，脑啡肽具有类似于 吗啡。纳络酮和纳洛酮的药理研究 纳洛酮是两种相对选择性较高的多药安慰剂。 这两种MU1受体亚型与不同阿片类药物的相关性 行为。例如，MUL受体在 脊髓上止痛，而MU2受体介导吗啡 抑制胃动素转运和呼吸抑制。 总而言之，药理学和约束性研究的能力 区分这两个子类型，有力地证明了他们的 存在。最近的研究还表明，存在亚型 Kappa受体。此应用程序建议检查概念 Mu和kappa受体的异质性。膜结合研究 将专注于开发各种不同的选择性检测方法 子类型，用于检查它们的选择性和 生化特征。高选择性多分子结合分析 现已可用，并将用于更全面地描述 药理选择性、地区分布、个体发育和 MUL受体的发展史。其他研究将检查最近的 证据表明形成了一种非常缓慢的联想 涉及G蛋白的受体构象通过多个步骤 进程。额外的调查可能会使用几个 本实验室合成的新型放射性配基亲和标记 MU2和kappa受体亚型及其特性 生化方面的。本申请书中建议的研究应 进一步了解Mu和kappa受体的异质性 而且，希望高度选择性的无痛疗法的发展 缺乏不良的阿片类药物副作用。

One of the most importance concepts to emerge in recent years in opiate research is the concept of multiple opioid receptors. Originally proposed as "Receptor Dualism", this concept has now been expanded to include a variety of pharmacologically-defined receptor classes. Recent studies suggest two subtypes of mu receptors. The mu2 site corresponse to the classical morphine- selective mu recePtor previously characterized in peripheral bioassays and in the brain. The mul receptor was first recognize in receptor binding studies and has a unique selectivity, finding most, but not all, enkephalins with high affinities similar to morphine. Pharmacological studies using naloxonazine and naloxazone, two relatively selective mul anragonisers, have correlated these two mu1 receptor subtypes with different opiate actions. For example, mul receptors play a major role in supraspinal analgesia whereas mu2 receptors mediate morphine's inhibition of Kastrointesinial transit and respiratory depression. Together, the ability of both pharmacological and binding studies to distinguish between these two subtypes argues strongly for their existence. Recent work also suggests the existence of subtypes of kappa receptors. This application proposes to examine the concept of mu and kappa receptor heterogeneity. Membrane binding studies will focus upon the development of selective assays for the various subtypes which when be used to examine their selectivity and biochemical characteristics. Highly selective mul binding assays are now available and will be used to characterize more fully the Pharmacological selectivity, regional distribution, ontogeny and phylogeny of mul receptors. Other studies will examine recent evidence suggesting the formation of a very slowly-associating receptor conformation involving G-Proteins through a multiste process. Additional investigations possibly will employ several new radioligands synthesized in our laboratory to affinity label both mu2 and kappa receptor subtypes and characterize them biochemically. The studies proposed in this application should further our understanding of mu and kappa receptor hetereokeneity and, hopefully, the development of highly selective anathesics lacking undesirable opioid side-effects.