Recent improvements in the development of A2B adenosine receptor agonists
Recent improvements in the development of A2B adenosine receptor agonists
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DOI：
10.1007/s11302-009-9140-8
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Preti, Delia
中科院分区：
文献类型：
--
作者：
Baraldi, Pier Giovanni;Tabrizi, Mojgan Aghazadeh;Preti, Delia
已知腺苷通过在四种受体亚型A（1）、A（2A）、A（2B）和A（3）（AR）上作为局部调节剂发挥其大部分生理功能。主要由于难以识别有效和选择性激动剂，A（2B）AR是腺苷受体家族中特征最不广泛的。尽管存在这些限制，但对该靶点的生理意义的日益了解表明特异性配体具有良好的治疗前景。由于A（2B）AR信号似乎与预/后处理心脏保护和抗炎机制相关，选择性激动剂可能代表冠状动脉疾病患者的新治疗组。在此，我们提出了一个概述，在确定有效的和选择性的A（2B）AR激动剂在科学和专利文献报道的最新进展。这些化合物可分为腺苷样和非腺苷配体。核苷类激动剂是通过在嘌呤杂环的N（6）-、C-2-位和/或核糖部分的5 ′-位或这些取代的组合进行取代而修饰腺苷的结果。化合物1-脱氧-1-{6-[N '-（呋喃-2-羰基）-肼基]-9H-嘌呤-9-基}-N-乙基-β-D-呋喃核糖苷酰胺（19，hA（1）K（i）= 1050 nM，hA（2A）K（i）= 1550 nM，hA（2B）EC 50 = 82 nM，hA（3）K（i）> 5 μ M）及其2-氯类似物23（hA（1）K（i）= 3500 nM，hA（2A）K（i）= 4950 nM，hA（2B）EC 50 = 210 nM，hA（3）K（i）> 5 μ M）在表达hA（2B）AR的中国仓鼠卵巢（CHO）细胞中的环磷酸腺苷（cAMP）功能测定中被证实是有效的和选择性的完全激动剂。非核糖配体以方便取代的二腈吡啶为代表，其中2-[6-氨基-3，5-二氰基-4-[4-（环丙基甲氧基）苯基]吡啶-2-基硫烷基]乙酰胺（BAY-60-6583，hA（1），hA（2A），hA（3）EC 50> 10 μ M; hA（2B）EC 50 = 3 nM）目前正在临床前阶段研究中用于治疗冠状动脉疾病和动脉粥样硬化。
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A(1), A(2A), A(2B) and A(3) (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A(2B) AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A(2B) AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A(2B) AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N (6)-, C-2-positions of the purine heterocycle and/or at the 5'-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N'-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-beta-D-ribofuranuronamide (19, hA(1) K (i) = 1050 nM, hA(2A) K (i) = 1550 nM, hA(2B) EC50 = 82 nM, hA(3) K (i) > 5 mu M) and its 2-chloro analogue 23 (hA(1) K (i) = 3500 nM, hA(2A) K (i) = 4950 nM, hA(2B) EC50 = 210 nM, hA(3) K (i) > 5 mu M) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA(2B) AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60-6583, hA(1), hA(2A), hA(3) EC50 > 10 mu M; hA(2B) EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.