CLASSIFICATION OF VASCULAR SMOOTH MUSCLE ALPHA-RECEPTORS

几种临床上用于治疗慢性阻塞性肺疾病的药物 心血管疾病作用于血管α1-肾上腺素受体。 重要的是，尤其是从药物设计的角度来看， 对这些受体进行分类和表征。这项建议是 朝向这一目标，并将导致更多的理解 与药物作用有关的分子事件。 在现有药理证据的基础上，建议 血管α1肾上腺素受体展示了物种、组织和 血管异质性。由于受体的分类 最终将涉及到对其药理作用的了解 性质和受体结构这一假设将被探索 使用这两个标准。 一系列α-肾上腺素能配体与α-1-的亲和力 将测定大鼠和兔动脉的肾上腺素能受体。 放射性配基结合实验。字母1的证据- 肾上腺素受体的异质性将来自配基的差异 关于效力和/或绝对等级顺序的亲和度 价值观。因为受体微环境的变化是 已知会影响两者的结合和内在活性 激动剂和拮抗剂，配体的亲和力将是 在破碎的细胞膜和溶解的洗涤剂中测定 受体制剂以及在已知 受体调节剂。如果是这样的话，这一假设就会得到支持 发现配体在这些条件下保留了它们的区别作用 条件。 其次，有可能区分不同的亚群 基于某些粗大分子的α1-肾上腺素能受体 它们的分子大小、等电点、 流体力学性质和糖蛋白性质。 这项建议是针对以下长期目标的 对血管受体和意志进行分类和充分表征 为艰巨的受体纯化任务奠定了基础。

Several drugs that are used clinically in the treatment of cardiovascular disease act at the vascular alpha1-adrenoceptors. It is important, especially from the stand-point of drug design, to classify and characterize these receptors. This proposal is directed toward this goal and will lead to a greater understanding of the molecular events involved in drug action. On the basis of current pharmacological evidence, it is proposed that vascular alpha1-adrenoceptors exhibit species, tissue and blood vessel heterogeneity. Since the classification of receptors will ultimately involve a knowledge of their pharmacological properties and receptor structure the hypothesis will be explored using these two criteria. The affinities of a series of alpha-adrenergic ligands for alpha1- adrenoceptors will be determined in rat and rabbit arteries in radioligand binding experiments. Evidence for alpha1- adrenoceptor heterogeneity will come from differences in ligand affinities with regard to rank order of potency and/or absolute values. Since variations in the receptors' microenvironment are known to affect the binding and intrinsic activities of both agonists and antagonists, the affinities of the ligands will be determined in broken cell membrane and detergent solubilized receptor preparations as well as in the presence of known receptor modulators. The hypothesis will be supported if it is found that ligands retain their discriminating actions under these conditions. Secondly, it may be possible to distinguish between subpopulations of alpha1-adrenoceptors on the basis of certain gross molecular parameters such as their molecular size, isoelectric points, hydrodynamic properties and glycoprotein nature. This proposal is directed toward the long-term objectives of classifying and fully characterizing vascular receptors and will form the basis for the arduous task of receptor purification.