STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,3-DIALKYLXANTHINE DERIVATIVES AT RAT A(3) ADENOSINE RECEPTORS

1,3-Dialkylxanthine analogues containing carboxylic acid and other charged groups on 8-position substituents were synthesized. These derivatives were examined for affinity in radioligand binding assays at rat brain A(3) adenosine receptors stably expressed in CHO cells using the new radioligand [I-125]AB-MECA (N-6-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide), and at rat brain A(1) and A(2a) receptors using [H-3]PIA and [H-3]CGS 21680, respectively. A synthetic strategy for introducing multiple carboxylate groups at the 8-position using iminodiacetic acid derivatives was explored. The presence of a sulfonate, a carboxylate, or multiple carboxylate soups did not result in a significant enhancement of affinity at rat A(3) receptors, although as previously observed an anionic group tended to diminish potency at Ar and A(2a) receptors. The rat A(3) receptor affnity was not highly dependent on the distance of a carboxylate group from the xanthine pharmacophore. 2-Thio vs 2-oxo substitution favored A(3) potency, and 8-alkyl vs 8-aryl substitution favored A(3) selectivity, although few derivatives were truly selective for rat A(3) receptors. 1,3-Dimethyl-8-(3-carboxypropyl)-2-thioxanthine was 7-fold selective for A(3) VS A(2)a receptors. 1,3,7-Trimethyl-8-(trans-2-carboxyvinyl) was somewhat selective for A(3) VS A(1) receptors. For 8-arylxanthines affinity at A(3) receptors was enhanced by 1,3-dialkyl substituents, in the order dibutyl > dipropyl > diallyl.