Acyl-Hydrazide Derivatives of a Xanthine Carboxylic Congener (XCC) as Selective Antagonists at Human A Adenosine Receptors.

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.