环腺苷二磷酸核糖(cADPR)类似物的合成与诱导钙释放活性的研究

Studies on Cyclic ADP-ribose (cADPR) Analogues: Synthesis and Calcium Release Activity

Ca2+信号传导通路是生物体内重要的胞内信号传导途径之一。局部钙信号主要来源于细胞内钙库释放,而这些钙信号受到各种第二信使的控制和Ca2+通道蛋白的调节。环腺苷二磷酸核糖(cADPR)作为烟酰胺腺嘌呤二核苷酸(NAD+)的代谢物,发现于1987年,是一种信号传导分子,它广泛存在于各种生物系统中,通过介导兰诺定(RyR)受体调节钙动员活性。研究cADPR以及具有不同生物活性的类似物之间的构效关系是探究分子内钙释放机制的主要手段,另外,一些结构新颖的拮抗剂和激动剂可以作为研究细胞系统复杂机制的研究工具。作者概括性地介绍了cADPR结构类似物——N1-乙氧基甲基-环肌苷-5'-二磷酸核糖(cIDPRE)和N1-[(磷酰基-O-乙氧基)-甲基-N9-[(磷酰基-O-乙氧基)-甲基-次黄嘌呤-环磷酸焦酯(cIDPDE)的合成与性质。这两种类似物cIDPDE和cIDPRE可作为研究完整细胞钙信号系统的膜透性激动剂。

Ca^2＋ signaling is one of the most important intracellular signal transduction pathways in diverse cells. Local Ca^2＋ signals are mainly due to release from internal stores and these calcium release events are controlled by various second messengers and regulated by Ca^2＋ channel-associated proteins. Cyclic ADP-ribose （cADPR）, a metabolite of NAD＋, was discovered in 1987 and is a signaling molecule to regulate calcium mobilization via ryanodine receptors （RyR） from intracellular stores in a wide variety of biological systems. A main approach to explore the molecular mechanism of calcium release is to investigate the relationship of the structure of cADPR and cADPR analogues with their respective biological activities. In addition to the structure activity relationship, such studies result in novel antagonists and agonists which serve as the tools for mechanistic studies in the complex cellular system. This review outlines the design and discovery of structural mimics of cADPR （cIDPRE and cIDPDE） with replacement of one or both of the ribose moieties by ether bridges. Compounds of the type cIDPDE or cIDPRE may thus both be used as membrane-permeant, agonists of the cADPR/Ca^2＋ signaling system in intact cells.