探索了8-苯基-1,3-二丙基黄嘌呤衍生物与重组人A2B腺苷受体结合的构效关系(SAR),以鉴定选择性拮抗剂。基于MRS1204中受体选择性的发现,包含通过8-苯基取代基的对位连接的N-羟基琥珀酰亚胺酯[Jacobson等人。(1999):药物开发。Ress.,47:45-53],合成了一种酰肼及其更稳定的酰亚胺衍生物。XCC的酰肼(8-[4-[[[羧基]甲基]氧基]苯基]-1,3-二丙基黄嘌呤)用多种一元和二元羧酸酰化。在腺苷受体结合测定中测定Ki值。在HEK-293细胞膜上表达的重组人A2B受体,使用的拮抗剂放射性配体是黄嘌呤125I-ABOPX(125I-3-(4-氨基-3-碘苄基)-8-氧乙酸酯-1-丙基-黄嘌呤)和非黄嘌呤拮抗剂[3H]ZM241385([3H]4-(2-[7-氨基-2-呋喃基}{1,2,4}三唑并{2,3,5-氨基)初步筛选利用大鼠A1/A2A受体和人A3受体,并在人A1/A2A亚型检查所选化合物。一种1,2-二甲基马来酰亚胺衍生物,14(MRS1595),与人A2B受体结合,Ki为19nM,被证明是选择性的。人A1/A2A/A3受体由160-,100-,35倍,分别。Enprofylline(3-丙基黄嘌呤)对A2B受体有轻微的选择性,建议去除1-丙基;然而,1-H-3-Pr和8-苯基取代基的组合消除了选择性。其他有效和中等选择性的A2B拮抗剂是四氢苯甲酰衍生物18b(MRS1614,Ki值10nM)和XCC-酰肼的氨基酸缀合物,即,戊二酰亚胺24b(MRS1626,Ki值13nM),和受保护的二肽27(MRS1615,Ki值11nM)。药物开发。Ress.47:178-188,1999.
The structure-activity relationships (SAR) of 8-phenyl-1,3-dipropylxanthine derivatives in binding to recombinant human A2B adenosine receptors were explored, in order to identify selective antagonists. Based on the finding of receptor selectivity in MRS 1204, containing an N-hydroxysuccinimide ester attached through the p-position of the 8-phenyl substituent [Jacobson et al. (1999): Drug Dev. Res., 47:45-53], a hydrazide and its more stable imide derivatives were synthesized. The hydrazide of XCC (8-[4-[[[carboxy]methyl]oxy]phenyl]-1,3-dipropylxanthine) was acylated with a variety of mono- and dicarboxylic acids. Ki values were determined in the adenosine receptor binding assays. At recombinant human A2B receptors expressed in membranes of HEK-293 cells, antagonist radioligands used were the xanthine 125I-ABOPX (125I-3-(4-amino-3-iodobenzyl)-8-oxyacetate-1-propyl-xanthine) and the nonxanthine antagonist [3H]ZM 241385 ([3H]4-(2-[7-amino-2-{furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-ylamino-ethyl)phenol). The initial screening utilized rat A1/A2A receptors and human A3 receptors, and selected compounds were examined at the human A1/A2A subtypes. A 1,2-dimethylmaleimide derivative, 14 (MRS 1595), bound to human A2B receptors with a Ki of 19 nM and proved to be selective vs. human A1/A2A/A3 receptors by 160-, 100-, and 35-fold, respectively. Enprofylline (3-propylxanthine) is slightly selective for A2B receptors, suggesting removal of the 1-propyl group; however, combination of the 1-H-3-Pr and 8-phenyl substituents eliminated the selectivity. Other potent and moderately selective A2B antagonists were a tetrahydrophthaloyl derivative 18b (MRS 1614, Ki value 10 nM) and amino acid conjugates of the XCC-hydrazide, i.e., the glutarimide 24b (MRS 1626, Ki value 13 nM), and protected dipeptide 27 (MRS 1615, Ki value 11 nM). Drug Dev. Res. 47:178-188, 1999.