Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A2B adenosine receptors
Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A2B adenosine receptors
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DOI：
10.1021/jm990421v
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发表时间：
2000-03-23
影响因子：
7.3
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Kim, YC;Ji, XD;Jacobson, KA
尚未报道 A(2B) 腺苷受体 (AR) 的高选择性拮抗剂；然而，此类拮抗剂具有作为抗哮喘剂的治疗潜力。在此，我们报告了有效且选择性的 A(2B) 受体拮抗剂的合成。探讨了 8-苯基-1,3-二-(正丙基)黄嘌呤衍生物在 HEK-293 细胞 (HEK-A(2B)) 和其他 AR 亚型中与重组人 A(2B) AR 结合的构效关系 (SAR)。合成了8-[4-[[羧甲基]氧基]苯基]-1,3-二-(正丙基)黄嘌呤4a的各种酰胺衍生物。芳基酰胺、烷基酰胺和芳烷基酰胺的比较表明，简单的苯胺，特别是在对位被吸电子基团（例如硝基、氰基和乙酰基）取代的苯胺，可以在 1-3 nM 范围内选择性地与人 A(2B) 受体结合。未取代的苯胺12对A(2B)受体的K-i值为1.48 nM，但对人A(1)/A(2A)受体仅具有中等选择性，对大鼠A(1)受体无选择性。高效且选择性的 A(2B) 拮抗剂是对氨基苯乙酮衍生物 20（K-i 值 1.39 nM）和对氰基苯胺 27（K-i 值 1.97 nM）。与人 A(1)/A(2A)/A(3) 受体相比，化合物 27 对人 A(2B) 受体的选择性分别是 400、245 和 123 倍，对大鼠 A(1)/A(2A) 受体的选择性分别是 8.5 和 310 倍。用 1,3-二乙基取代 1,3-二丙基对选择性没有不利影响，并且保持了对 A(2B) 受体的高亲和力。用丙烯酸取代 4a 的对羧甲基氧基及其酰胺，降低了对 A(2B) 受体的亲和力，同时增加了对 A(1) 受体的亲和力。尽管对羧甲基氧基衍生物 9 对 A(2B) 受体具有中等选择性，但 1,3-二（环己基甲基）基团大大降低了 AR 的亲和力。几种选择性 A(2B) 拮抗剂抑制 HEK-A(2B) 细胞中 NECA 刺激的钙动员。
No highly selective antagonists of the A(2B) adenosine receptor (AR) have been reported; however such antagonists have therapeutic potential as antiasthmatic agents. Here we report the synthesis of potent and selective A(2B) receptor antagonists. The structure-activity relationships (SAR) of 8-phenyl-1,3-di-(n-propyl)xanthine derivatives in binding to recombinant human A(2B) ARs in HEK-293 cells (HEK-A(2B)) and at other AR subtypes were explored. Various amide derivatives of 8-[4-[[carboxymethyl]oxy]phenyl]-1,3-di-(n-propyl)xanthine, 4a, were synthesized. A comparison of aryl, alkyl, and aralkyl amides demonstrated that simple anilides, particularly those substituted in the para-position with electron-withdrawing groups, such as nitro, cyano, and acetyl, bind selectively to human A(2B) receptors in the range of 1-3 nM. The unsubstituted anilide 12 had a K-i value at A(2B) receptors of 1.48 nM but was only moderately selective versus human A(1)/A(2A) receptors and nonselective versus rat A(1) receptors. Highly potent and selective A(2B) antagonists were a p-aminoacetophenone derivative 20 (K-i value 1.39 nM) and a p-cyanoanilide 27 (K-i value 1.97 nM). Compound 27 was 400-, 245-, and 123-fold selective for human A(2B) receptors versus human A(1)/A(2A)/A(3) receptors, respectively, and 8.5- and 310-fold selective versus rat A(1)/A(2A) receptors, respectively. Substitution of the 1,3-dipropyl groups with 1,3-diethyl offered no disadvantage for selectivity, and high affinities at A(2B) receptors were maintained. Substitution of the p-carboxymethyloxy group of 4a and its amides with acrylic acid decreased affinity at A(2B) receptors while increasing affinity at A(1) receptors. 1,3-Di(cyclohexylmethyl) groups greatly reduced affinity at ARs, although the p-carboxymethyloxy derivative 9 was moderately selective for A(2B) receptors. Several selective A(2B) antagonists inhibited NECA-stimulated calcium mobilization in HEK-A(2B) cells.