Kim Yong-Chul, Karton Yishai, Ji Xiao-Duo, Melman Neli, Linden Joel, Jacobson Kenneth A
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Department of Chemistry, Israel Institute of Biological Research, Ness Ziona, Israel.
Drug Dev Res. 1999 Aug;47(4):178-188. doi: 10.1002/(sici)1098-2299(199908)47:4<178::aid-ddr4>3.0.co;2-l.
The structure-activity relationships (SAR) of 8-phenyl-1,3-dipropylxanthine derivatives in binding to recombinant human A 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 -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. K values were determined in the adenosine receptor binding assays. At recombinant human A receptors expressed in membranes of HEK-293 cells, antagonist radioligands used were the xanthine I-ABOPX (I-3-(4-amino-3-iodobenzyl)-8-oxyacetate-1-propyl-xanthine) and the nonxanthine antagonist [H]ZM 241385 ([H]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 A/A receptors and human A receptors, and selected compounds were examined at the human A/A subtypes. A 1,2-dimethylmaleimide derivative, (MRS 1595), bound to human A receptors with a Ki of 19 nM and proved to be selective vs. human A/A/A receptors by 160-, 100-, and 35-fold, respectively. Enprofylline (3-propylxanthine) is slightly selective for A 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 A antagonists were a tetrahydrophthaloyl derivative (MRS 1614, K value 10 nM) and amino acid conjugates of the XCC-hydrazide, i.e., the glutarimide (MRS 1626, K value 13 nM), and protected dipeptide (MRS 1615, K value 11 nM). Drug Dev. Res. 47:178-188, 1999.
为了确定选择性拮抗剂，研究了8-苯基-1,3-二丙基黄嘌呤衍生物与重组人A腺苷受体结合的构效关系（SAR）。基于在MRS 1204中发现的受体选择性，该化合物含有通过8-苯基取代基的β位连接的N-羟基琥珀酰亚胺酯[Jacobson等人（1999年）：药物研发，47:45 - 53]，合成了一种酰肼及其更稳定的酰亚胺衍生物。XCC（8-[4-[[[羧基]甲基]氧基]苯基]-1,3-二丙基黄嘌呤）的酰肼用多种一元和二元羧酸进行酰化。在腺苷受体结合试验中测定K值。在HEK-293细胞膜中表达的重组人A受体上，使用的拮抗剂放射性配体是黄嘌呤I-ABOPX（I-3-(4-氨基-3-碘苄基)-8-氧代乙酸-1-丙基-黄嘌呤）和非黄嘌呤拮抗剂[H]ZM 241385（[H]4-(2-[7-氨基-2-{呋喃基}{1,2,4}三唑并{2,3-a}{1,3,5}三嗪-5-基氨基-乙基)苯酚）。初始筛选利用大鼠A/A受体和人A受体，对选定的化合物在人A/A亚型上进行检测。一种1,2-二甲基马来酰亚胺衍生物（MRS 1595）与人A受体结合，Ki为19 nM，相对于人A/A/A受体分别具有160倍、100倍和35倍的选择性。恩丙茶碱（3-丙基黄嘌呤）对A受体有轻微选择性，表明去除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。其他强效且中等选择性的A拮抗剂是一种四氢邻苯二甲酰衍生物（MRS 1614，K值10 nM）以及XCC-酰肼的氨基酸缀合物，即戊二酰亚胺（MRS 1626，K值13 nM）和受保护的二肽（MRS 1615，K值11 nM）。药物研发，47:178 - 188，1999年。
