CLASSIFICATION OF VASCULAR SMOOTH MUSCLE ALPHA-RECEPTORS

临床上用于治疗的几种药物 心血管疾病作用于血管α 1-肾上腺素受体。 重要的是，特别是从药物设计的角度来看， 分类和表征这些受体。 这项建议是 并将导致更好的理解 药物作用中的分子事件。 根据目前的药理学证据，建议 血管α 1-肾上腺素受体表现出物种、组织和 血管异质性 由于受体的分类 最终会涉及到他们的药理学知识， 性质和受体结构的假设将进行探讨 根据这两个标准。 一系列α-肾上腺素能配体对α 1- 将在大鼠和兔动脉中测定肾上腺素受体， 放射性配体结合实验。 关于alpha 1- 肾上腺素受体的异质性来自于配体的差异 关于效力和/或绝对值的等级顺序的亲和力 价值观 由于受体微环境的变化， 已知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去污剂中测定 受体制剂以及在已知的 受体调节剂。 假设将得到支持，如果它是 发现配体在这些条件下保留了它们的识别作用， 条件 第二，可以区分亚群 基于某些总分子的α 1-肾上腺素受体 参数如它们的分子大小，等电点， 流体动力学性质和糖蛋白性质。 本建议旨在实现以下长期目标： 分类和充分表征血管受体， 形成了艰巨的受体纯化任务的基础。

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.