MAPPING ADENOSINE RECEPTORS FOR RATIONAL DRUG DESIGN

腺苷被认为是一种激素，对大多数 高等生物的细胞。尽管广泛而重要的 腺苷、激动剂和药物的生理和病理效应 腺苷受体的拮抗剂尚未被广泛开发用于 出于制药目的。 这项计划的长远目标是合理设计 腺苷受体特异性药物。为此，目前的研究是 设计用于确定腺苷和黄嘌呤的结合口袋 A1-和A2-腺苷受体及其空间排列的理解 这些受体中的一个。这些受体已经被克隆，并将被过度- 表达以获得足够的材料来研究 分子水平。具体地说，此应用程序建议将 通过亲和标记腺苷受体中的几个位置 配基结合位点和鉴定随后产生的片段 感受器。基于该结构的光亲和亲和探针 激动剂和拮抗剂都将被设计来标记核糖- 结合结构域、N6-芳烷基结合结构域和2-芳烷氧基结合 激动剂的结构域和有效的8-环烷基部分的结构域 黄嘌呤拮抗剂。此外，将使用代理，这将有助于 辨认出与嘌呤结合的口袋。

Adenosine is considered to be a hormone with localized effects on most cells of higher organisms. Despite the widespread and important physiological and pathological effects of adenosine, agonists and antagonists of the adenosine receptors have not been widely exploited for pharmaceutical purposes. The long-range objective of this program is the rational design of adenosine receptor-specific drugs. Toward this end the current research is designed to determine the adenosine and xanthine binding-pockets of the A1- and A2-adenosine receptors and to understand the spatial arrangement of these receptors. These receptors have been cloned and will be over- expressed to obtain sufficient material to study the receptors at the molecular level. Specifically, this application proposes to map the adenosine receptors by affinity-labeling several locations within the ligand binding sites and identifying subsequently generated fragments of the receptors. Photoaffinity and affinity probes based on the structures of both agonists and antagonists will be designed to label the ribose- binding domain, the N6-aralkyl-binding domain and the 2-aralkoxy-binding domain of agonists and the domain for the 8-cycloalkyl moiety of potent xanthine antagonists. In addition, agents will be used that should help identify the purine-binding pocket.