Cyclic AMP-dependent inhibition of human neutrophil oxidative activity by substituted 2-propynylcyclohexyl adenosine A2A receptor agonists
Cyclic AMP-dependent inhibition of human neutrophil oxidative activity by substituted 2-propynylcyclohexyl adenosine A2A receptor agonists
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DOI：
10.1038/sj.bjp.0703893
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发表时间：
2001-03-01
影响因子：
7.3
通讯作者：
Linden, J
中科院分区：
文献类型：
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作者：
Sullivan, GW;Rieger, JM;Linden, J
在环己基环4位反式取代的新型2-丙基环己基-5′- n -乙基羧氨基腺苷与四种亚型腺苷受体（ARs）的结合试验中进行了评价。4-{3-[6-氨基-9-（5-乙基氨基-3,4-二羟基四氢呋喃-2-基）- 9h -嘌呤-2-基]-丙-2-炔基}-环己酸甲酯（ATL146e）和乙酸4-{3-[6-氨基-9-（5-乙基氨基-3,4-二羟基四氢呋喃-2-基）- 9h -嘌呤-2-基]-丙-2-炔基}-环己基甲酯（ATL193）对人AZA - AR的结合效能比2-[4-（2-羧基乙基）苯乙胺]-5'- n-乙基羧氨基腺苷（CGS21680）强50倍。人A - A - AR对取代环己基丙基腺苷类似物的亲和力与环己基侧链的极性呈负相关。a的效力顺序相似：a - AR激动剂刺激人中性粒细胞[环AMP](i)，抑制中性粒细胞氧化破裂。ATL146e和CGS21680与人A(3) ars的等效激动剂相似我们测量了选择性AR拮抗剂对激动剂刺激的中性粒细胞[环AMP]的影响(i)和PKA抑制对A(2A) AR激动剂活性的影响。atl193刺激的中性细胞[环AMP](i)被拮抗剂阻断，其效价顺序为：ZM241385 （A(2A)-选择性）> MRS1220 （A(3)-选择性）> > N-（4-（2,6-二氧基-1,3-二丙基- 2,3,4,5,6,7-六氢- 1h -嘌呤-8-基）-苯氧基）-乙酰胺（MRS1754； A(2B)-选择性）近似于8-（N-甲基异丙基）氨基-N-6-（5'-内羟基-内源性鸟脑酰基）-9-甲基腺嘌呤（WRC0571； A(1)-选择性）。IV型磷酸二酯酶抑制剂罗利普兰（100 nM）增强了ATL193对氧化爆发的抑制作用，而ATL193的抑制作用被PKA抑制剂H-89.3抵消。数据表明，A(2A)ARs的激活通过激活[环AMP](i)/PKA抑制中性粒细胞氧化活性。
1 Novel 2-prupynylcyclohexyl-5'-N-ehtylcarboxamidoadenosines, trans-substituted in the 4-position of the cyclohexyl ring, were evaluated in binding assays to the four subtypes of adenosine receptors (ARs). Two esters, 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL146e) and acetic acid 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexylmethyl ester (ATL193) were > 50 x more potent than 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) for human AZA AR binding. Human A A AR affinity for substituted cyclohexyl-propynyladenosine analogues was inversely correlated with the polarity of the cyclohexyl side chain. There was a comparable order of potency for A:A AR agonist stimulation of human neutrophil [cyclic AMP](i), and inhibition of the neutrophil oxidative burst. ATL146e and CGS21680 were similar to equipotent agonists of human A(3) ARs.2 We measured the effects of selective AR antagonists on agonist stimulated neutrophil [cyclic AMP](i) and the effect of PKA inhibition on A(2A) AR agonist activity. ATL193-stimulated neutrophil [cyclic AMP](i) was blocked by antagonists with the potency order: ZM241385 (A(2A)- selective)> MRS1220 (A(3)-selective)> > N-(4-Cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl- 2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]-acetamide (MRS1754; A(2B)-selective) approximate to 8-(N-methylisopropyl)amino-N-6-(5'-endohydroxy-endonorbornyl)-9-mthyladenine (WRC0571; A(1)-selective). The type IV phosphodiesterase inhibitor, rolipram (100 nM) potentiated ATL193 inhibition of the oxidative burst, and inhibition by ATL193 was counteracted by the PKA inhibitor H-89.3 The data indicate that activation of A(2A)ARs inhibits neutrophil oxidative activity by activating [cyclic AMP](i)/PKA.