A quantitative analysis of binding affinities of ligands active at adenosine receptors

Binding affinities, pKi's, of 1,3-dipropyl-8-phenylxanthines and 8-substituted xanthines as selective antagonists at A(1)- and A(2)- adenosine receptors, were quantitatively analysed in terms of hydrophobic parameter, pi, and van der Waals volume, Vw. For ligands of the first series, the hydrophobicity of para-substituents and the bulk of meta-substituents are shown to be the deciding factors. Similarly, for the other series, the binary substitutions at X-, Y- and R-positions, highlighted by respective dummy variables, and the bulk rendered by groups at R(1)-position, are found to be significantly correlated with A(1)- and A(2)-receptor affinities. Additionally, the Free-Wilson study of this series resulting into individual substituent contribution, provides similar inferences to these, but in a more exact manner. This study also hints at the possibility of a different accommodation site at the receptor for the R(1)-substituents of the congeners on account of conformational dissimilarity of A(1)- and A(2)-receptors.