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三氟甲基及其他取代基对黄嘌呤类化合物在腺苷受体上活性的影响。

Effect of trifluoromethyl and other substituents on activity of xanthines at adenosine receptors.

作者信息

Jacobson K A, Shi D, Gallo-Rodriguez C, Manning M, Müller C, Daly J W, Neumeyer J L, Kiriasis L, Pfleiderer W

机构信息

Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892.

出版信息

J Med Chem. 1993 Sep 3;36(18):2639-44. doi: 10.1021/jm00070a007.

DOI:10.1021/jm00070a007
PMID:8410976
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12445928/
Abstract

An aryl p-(trifluoromethyl) substituent increases the affinity of 1,3-disubstituted 8-phenylxanthines at A2a-adenosine receptors, while having little effect on affinity at A1-adenosine receptors. In contrast, an aryl p-(trifluoromethyl) substituent has little effect on affinity of 3,7-disubstituted and 1,3,7-trisubstituted 8-phenylxanthines. An aryl p-sulfo substituent reduces affinity of all 8-phenylxanthines at A1- and A2a-adenosine receptors. An 8-(trifluoromethyl) substituent markedly reduces affinity of 1,3-dialkylxanthines at both A1- and A2a-adenosine receptors. In contrast, 8-(trifluoromethyl)caffeine retains affinity for A2a-adenosine receptors, but does lose affinity for A1-adenosine receptors. 8-Bromo-, 8-acryl-, and 8-pent-1-enylcaffeines are also selective for A2-adenosine receptors, while 8-cyclobutylcaffeine is nonselective. 8-[trans-2-(tert-butyloxycarbonyl)vinylcaffeine is 20-fold selective for Aza vs A1 receptors.

摘要

芳基对（三氟甲基）取代基可增加1,3 - 二取代8 - 苯基黄嘌呤对A2a - 腺苷受体的亲和力，而对其对A1 - 腺苷受体的亲和力影响较小。相比之下，芳基对（三氟甲基）取代基对3,7 - 二取代和1,3,7 - 三取代8 - 苯基黄嘌呤的亲和力影响较小。芳基对磺基取代基会降低所有8 - 苯基黄嘌呤对A1 - 和A2a - 腺苷受体的亲和力。8 - （三氟甲基）取代基会显著降低1,3 - 二烷基黄嘌呤对A1 - 和A2a - 腺苷受体的亲和力。相比之下，8 - （三氟甲基）咖啡因对A2a - 腺苷受体仍保留亲和力，但对A1 - 腺苷受体则失去亲和力。8 - 溴 - 、8 - 丙烯基 - 和8 - 戊 - 1 - 烯基咖啡因对A2 - 腺苷受体也具有选择性，而8 - 环丁基咖啡因则无选择性。8 - [反式 - 2 - （叔丁氧羰基）乙烯基]咖啡因对A2a受体与A1受体的选择性为20倍。

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本文引用的文献

1
Structure-activity relationships of 8-styrylxanthines as A2-selective adenosine antagonists.8-苯乙烯基黄嘌呤作为A2选择性腺苷拮抗剂的构效关系
J Med Chem. 1993 May 14;36(10):1333-42. doi: 10.1021/jm00062a005.
2
Adenosine receptor binding: structure-activity analysis generates extremely potent xanthine antagonists.腺苷受体结合：构效分析产生了极具效力的黄嘌呤拮抗剂。
Proc Natl Acad Sci U S A. 1983 Apr;80(7):2077-80. doi: 10.1073/pnas.80.7.2077.
3
Adenosine antagonism by purines, pteridines and benzopteridines in human fibroblasts.嘌呤、蝶啶和苯并蝶啶对人成纤维细胞中腺苷的拮抗作用。
Biochem Pharmacol. 1981 Feb 15;30(4):325-33. doi: 10.1016/0006-2952(81)90062-9.
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Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.抑制常数（K1）与导致酶促反应50%抑制率（I50）的抑制剂浓度之间的关系。
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108. doi: 10.1016/0006-2952(73)90196-2.
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