BIOCHEMICAL CHARACTERIZATION OF OPIATE BINDING SITES

近年来出现的最重要的概念之一， 阿片类药物的研究是多种阿片受体的概念。 这个概念最初被称为“接受者二元论”，现在已经 已扩展到包括各种药理学定义的 受体类别 最近的研究表明mu的两种亚型 受体。 μ 2位点对应于经典的吗啡- 先前在外周中表征的选择性μ受体 生物测定和大脑中。 穆尔受体首先被发现 在受体结合研究中具有独特的选择性， 大多数，但不是全部，具有高亲和力的脑啡肽类似于 吗啡 使用纳洛嗪和 纳洛沙宗是两种相对选择性的穆尔拮抗剂， 这两种mu 1受体亚型与不同的阿片类药物相关 行动 例如，穆尔受体在细胞凋亡中起主要作用。 脊髓上镇痛，而μ 2受体介导吗啡的 抑制Kastrointesinial运输和呼吸抑制。 总之，药理学和结合研究的能力 为了区分这两种亚型， 存在 最近的研究还表明， κ受体 本申请案建议检视以下概念 mu和kappa受体的异质性。 膜结合研究 将集中在发展的选择性测定的各种 当用于检查其选择性时， 生化特性 高选择性穆尔结合试验 现在可以使用，并将用于更全面地描述 药理学选择性、区域分布、个体发育和 穆尔受体的遗传。 其他研究将检查最近的 有证据表明， 受体构象涉及G-蛋白通过多级 过程 进一步的调查可能会雇用几个 我们实验室合成了新的放射性配体， mu 2和kappa受体亚型，并表征它们 生物化学 本申请中提出的研究应 进一步加深了我们对mu和kappa受体异质性的理解 希望能开发出高选择性镇痛药 没有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.