Effect of trifluoromethyl and other substituents on activity of xanthines at adenosine receptors.
Effect of trifluoromethyl and other substituents on activity of xanthines at adenosine receptors.
复制标题
三氟甲基和其他取代基对腺苷受体黄嘌呤活性的影响。
DOI：
10.1021/jm00070a007
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发表时间：
1993
影响因子：
7.3
通讯作者：
Pfleiderer,W
中科院分区：
文献类型：
--
作者：
Jacobson,KA;Shi,D;Gallo-Rodriguez,C;ManningJr,M;Müller,C;Daly,JW;Neumeyer,JL;Kiriasis,L;Pfleiderer,W
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-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. Anaryl p-sulfo substituent reduces affinity of all 8-phenylxanthines at-and Aņádenosme receptors. An 8-(trifluoromethyl) substituent markedly reduces affinity of 1, 3-dialkylxanthines at both-and A2a-adenosine receptors. In contrast, 8-(trifluoromethyl) caffeine retains affinity for Aņádenosme receptors, but does lose affinity for-adenosine receptors. 8-Bromo-, 8-acryl-, and 8-pent-1-enylcaffeines are also selective for A2-adenosine receptors, while 8-cyclobutylcaffeine is nonselective. 8-[troros-2-(tert-butyloxycarbonyl) vinylcaffeine is 20-fold selective for Aza vs receptors.Structure-activity relationships for xanthines as adenosine receptor antagonists havebeen studied extensively over the last 2 decades. 1 High potency in xanthines that retain moderate water solubility and, hence, bioavailability and high selectivity for different classes of adenosine receptors have been the goals of such studies. Addition of an 8-phenyl substituent, particularly for 1, 3-dipropylxanthines, yields extremely potent compounds with high selectivity for-adenosine receptors. 2-13 Unfortunately, many of these 8-phenylxanthines have extremely low water solubility and hence poor bioavailability. 14 The 8-cy-cloalkylxanthines proved to be more water soluble and to be both very potent and selective for-adenosine receptors. Xanthines with high selectivity for Aņáden-osme receptors had not been forthcoming, although certain 1.3. 7-trisubstituted xanthines exhibited modest selectivity for A2-adenosine receptors. 15· 16 Recently certain 8-styryl-1.3. 7-trisubstituted xanthines were reported to be highly selective for A2-adenosine receptors. 17· 18 The effects of aryl substituents on the potency and selectivity of 8-phenyltheophylline have been analyzed. In one study on bovine brain receptors a quantitative structure-activity analysis for 45 aryl-substituted 8-phe-nyltheophyllines was presented. 4 This study was preceded by a more limited exploration of structure-activity rela-tionships for aryl substituted 8-phenyltheophyllines. 3 Small electron-donating substituents at the ortho-position increased potency, while effects of para-substituents on activity were not readily correlated with electronic or steric effects or lipophilicity. Meta-substituentstended to decrease activity. Polar substituents such as p-sulfo or p-carboxy that are electron-withdrawing reduced potency at both-and A2-adenosine receptors, while conferring high water solubility. Ū Such xanthines have proven useful as peripheral adenosine receptor antagonists. 16· 19
