New 9-methyl-8-(4-hydroxyphenyl)adenine derivatives as A1 adenosine receptor antagonists

Abstract

A new series of 9-methyladenines, bearing different bulky groups at the 8-position, were prepared and their affinity for the four human adenosine receptor subtypes were evaluated. All the synthesized compounds showed affinities at the A1, A2A, and A3AR subtypes ranging from nanomolar to micromolar levels with different degrees of A1selectivity, while they resulted nearly inactive at A2BAR. In particular, 9-methyl-8-[4-(4-methylbenzyloxy)phenyl]- adenine showed A1AR affinity in the nanomolar range and good levels of selectivity versus the other receptor subtypes. Furthermore, a functional assay at mouse ileum allowed to assess the potency of selected compounds at A1AR subtype. Results showed that all the tested derivatives are neutral antagonists and theirKbvalues are in good agreement with theKivalues from radioligand binding assay at human A1AR, confirming that the effect is due to inhibition of this subtype.