Acyl-hydrazide derivatives of a xanthine carboxylic congener (XCC) as selective antagonists at human A2B adenosine receptors

✍ Scribed by Yong-Chul Kim; Yishai Karton; Xiao-duo Ji; Neli Melman; Joel Linden; Kenneth A. Jacobson

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 334 KB
• Volume: 47
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199908)47:4<178::aid-ddr4>3.0.co;2-l

✦ Synopsis

The structure-activity relationships (SAR) of 8-phenyl-1,3-dipropylxanthine derivatives in binding to recombinant human A 2B 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 : Drug Dev. Res., 47:45-53], a hydrazide and its more stable imide derivatives were synthesized. The hydrazide of methyl]oxy]phenyl]-1,3-dipropylxanthine) was acylated with a variety of mono-and dicarboxylic acids. K i values were determined in the adenosine receptor binding assays. At recombinant human A 2B receptors expressed in membranes of HEK-293 cells, antagonist radioligands used were the xanthine 125 I-ABOPX ( 125 I-3-(4-amino-3-iodobenzyl)-8-oxyacetate-1-propyl-xanthine) and the nonxanthine antagonist [ 3 H]ZM 241385 ([ 3 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 1 /A 2A receptors and human A 3 receptors, and selected compounds were examined at the human A 1 /A 2A subtypes. A 1,2-dimethylmaleimide derivative, 14 (MRS 1595), bound to human A 2B receptors with a K i of 19 nM and proved to be selective vs. human A 1 /A 2A /A 3 receptors by 160-, 100-, and 35-fold, respectively. Enprofylline (3-propylxanthine) is slightly selective for A 2B 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 2B antagonists were a tetrahydrophthaloyl derivative 18b (MRS 1614, K i value 10 nM) and amino acid conjugates of the XCC-hydrazide, i.e., the glutarimide