BIOCHEMICAL CHARACTERIZATION OF OPIATE BINDING SITES

近年来在鸦片类药物中出现的最重要的概念之一 研究的是多种阿片类药物结合位点的可能性。 这一概念最初被称为“受体二元论”，后来又被扩展。 为了说明三种药物产生的不同药理综合征 阿片剂的一般类别(MU、Kappa和Sigma)，最后是 脑啡肽(Delta)。不久之后，对约束的研究 所有这些类别的放射性标记药物的特征都产生了 结果与结合部位的异质性一致。我们建议继续 我们对这些生物化学特性的研究 假设的结合亚型，此外，试图将不同的 具有药理作用的结合部位。这种关联是我们的 终极目标。结合位点本身几乎没有相关性，除非它们可以 有助于理解药物的药理特性。我们, 因此，计划在体外和体内两种方法来解决这个问题。在……里面 在体外，我们将研究一些结合特性 四大类(MU、Kappa、sigma和Sigma)的放射性标记药物 Delta)。将使用两种一般技术。首先，我们将研究 脑匀浆中的结合。不同的配体将被比较 从药理和生化角度来看。其他研究将探讨 可能受体亚型的发育表型和系统发育 不同之处。我们还计划用同样的方法进行放射自显影 配基。同样，我们将从药理学和生化学的角度对它们进行比较。 然而，放射自显影技术使我们能够研究 通过匀浆研究无法获得的受体水平。这是 很重要。其他实验室已经显示出显著的差异 Mu和Delta结合位点的区域定位。我们还计划 调查一系列长效阿片激动剂和 体外和体内的拮抗剂。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，并使用这些结果来 将它们的操作与可能的绑定子类型相关联。最终，这些 研究将有望使我们更好地理解疼痛及其 控制力。

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.