Medicinal Chemistry of A3 Adenosine Receptor Modulators: Pharmacological Activities and Therapeutic Implications
Medicinal Chemistry of A3 Adenosine Receptor Modulators: Pharmacological Activities and Therapeutic Implications
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DOI：
10.1021/jm300087j
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发表时间：
2012-06-28
影响因子：
7.3
通讯作者：
Varani, Katia
中科院分区：
文献类型：
--
作者：
Baraldi, Pier Giovanni;Preti, Delia;Varani, Katia
嘌呤核苷腺苷被鉴定为不同组织和细胞功能的普遍存在的分子调节剂。1腺苷是在细胞外空间通过一系列胞外酶（包括腺苷三磷酸双磷酸酶和胞外5′-核苷酸酶）分解5′-三磷酸腺苷（ATP）而产生的。2在细胞内，腺苷被腺苷激酶磷酸化为腺苷5′-一磷酸（AMP），或被腺苷脱氨酶降解为肌苷。3 AMP水解产生腺苷是由胞质5′-核苷酸酶或S-腺苷高半胱氨酸水解介导的。[3]组织液中的腺苷水平在20 - 200 nM范围内，即使在代谢不利的条件下显著增加。4腺苷效应广泛存在，与腺苷受体（Adenosine receptor，AR）亚型的表达密切相关，这些受体亚型可以共表达，在细胞信号转导中起积极的调节作用。5 AR的特征在于通过不同的细胞内和细胞外环连接的七个跨膜结构域。4通过与百日咳毒素敏感的G蛋白家族的各种成员相互作用的A1 AR刺激调节不同的细胞效应物，如腺苷酸环化酶（AC）和磷脂酶C（PLC）。4. A2 A和A2 BAR通过与Gs蛋白偶联激活AC并增加cAMP水平。4 A3 AR通过与Gi蛋白的相互作用，抑制腺苷酸环化酶，降低环AMP积累和蛋白激酶A（PKA）活性。此外，A3 AR通过与Gq蛋白偶联，刺激PLC，引起细胞内钙水平的增加，并调节蛋白激酶C（PKC）活性。6从分子水平上看，A3 AR C端组氨酸残基的存在是细胞信号转导机制的关键。此外，丝氨酸和苏氨酸残基的存在涉及受体的脱敏和下调。有相当多的证据表明A3 AR调节丝裂原活化激酶（MAPK）的调节途径，所述丝裂原活化激酶包括细胞外信号调节激酶（ERK）、c-Jun N-末端激酶（JNK）和p38激酶。4已经报道了A3 AR激活对不同细胞中Akt/Ras/Raf/MEK/ERK信号通路调节的不同影响（图1）。8 A3 AR与缺氧诱导因子1α（HIF-1α）之间的强联系非常明显，HIF-1α是调节缺氧细胞反应的主要转录因子。9据报道，MAPK通路由A3 AR通过反馈机制调节，该反馈机制控制G蛋白偶联受体激酶2（GRK 2）活性并涉及特异性受体磷酸化。10 A3 AR的激活通过与受体对GRK介导的磷酸化的敏感性相关的易位引起抑制蛋白3在质膜中的积累。10据报道，短时间（约10分钟）的激动剂暴露导致A3 AR快速内化和功能性脱敏，如通过减少毛喉素刺激的AC的抑制所观察到的。11用A3 AR激动剂延长治疗约20小时诱导受体解偶联和与受体下调相关的功能性脱敏。11尽管有这种A3 AR脱敏，但腺苷酸环化酶活性并没有降低，如在毛喉素刺激存在下进行的实验所观察到的。此外，激动剂的去除介导，在约35分钟内，受体功能的恢复和再循环到质膜。
The purine nucleoside adenosine is identified as a ubiquitous molecule regulator of different tissues and cell functions. 1 Adenosine is generated in the extracellular space by the breakdown of adenosine 5′-triphosphate (ATP) through a series of ectoenzymes, including apyrase and ecto-5′-nucleotidase. 2 Inside the cell, adenosine is phosphorylated to adenosine 5′-monophosphate (AMP) by adenosine kinase or degraded to inosine by adenosine deaminase. 3 Adenosine production from the hydrolysis of AMP is mediated by a cytosolic 5′-nucleotidase or by the hydrolysis of S-adenosylhomocysteine. 3 The levels of adenosine in the interstitial fluid are in the range 20− 200 nM even if dramatically increased under metabolically unfavorable conditions. 4 Adenosine effects are widespread and closely associated with the expression of different adenosine receptor (AR) subtypes which can be coexpressed and serve as active modulators in the cell signaling transduction. 5 ARs are characterized by seven transmembrane domains connected by different intracellular and extracellular loops. 4 A1AR stimulation through the interaction with various members of pertussis toxin-sensitive family of G proteins modulates different cellular effectors as adenylate cyclase (AC) and phospholypase C (PLC). 4 The A2A and A2BARs through coupling with Gs proteins activate AC and increase cyclic AMP levels. 4 A3ARs, via the interaction with Gi proteins, inhibit adenylate cyclase, decreasing cyclic AMP accumulation and protein kinase A (PKA) activity. In addition, A3ARs, by coupling with Gq proteins, stimulate PLC, causing an increase of calcium levels from intracellular stores, and modulate the protein kinase C (PKC) activity. 6 From the molecular point of view, the presence of histidine residues at the C-terminus of A3ARs is responsible for the cell signaling transduction mechanisms. In addition, the presence of serine and threonine residues is involved in the desensitization and downregulation of the receptors. 7 There is considerable evidence for A3ARs to modulate the regulatory pathways of the mitogenactivated kinases (MAPKs) that consist of the extracellular signal regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and the p38 kinases. 4 Different effects of A3AR activation on the Akt/Ras/Raf/MEK/ERK signaling pathway modulation in different cells have been reported (Figure 1). 8 A strong link is well evident between A3ARs and hypoxia inducible factor 1α (HIF-1α), signaling that represents the main transcription factor regulating the cellular responses in hypoxia. 9 It is well reported that the MAPK pathway is regulated by A3ARs through a feedback mechanism that controls G-protein-coupled receptor kinase 2 (GRK2) activity and involves a specific receptor phosphorylation. 10 The activation of A3ARs causes the accumulation of arrestin 3 in plasma membranes through the translocation correlated with receptor sensitivity to GRK-mediated phosphorylation. 10It has been reported that a short time, about 10 min, of agonist exposure results in a rapid A3AR internalization and in a functional desensitization as observed by the reduction of the inhibition of forskolin-stimulated AC. 11 A prolonged treatment, about 20 h, with the A3AR agonists induces uncoupling of the receptor and functional desensitization associated with the receptor down-regulation. 11 Despite this A3AR desensitization, the adenylate cyclase activity is not reduced as observed from experiments performed in the presence of forskolin stimulation. In addition, the removal of the agonists mediates, in about 35 min, a restoration of the receptor functionality and recycling to plasma membrane …