Abstract
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 [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(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 Ki 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 24b (MRS 1626, K(i) value 13 nM), and protected dipeptide 27 (MRS 1615, K(i) value 11 nM). Drug Dev. Res. 47:178-188, 1999.