Adenosine receptors (ARs) are members of the superfamily of G protein-coupled receptors (GPCRs). There are four subtypes currently recognized: the A1AR, A2AAR, A2BAR and A3AR.
The classical AR antagonist caffeine is the most consumed drug in the world. Its effects on the nervous system, such as enhancement of awareness and learning, have encouraged the investigation of selective AR antagonists for the treatment of various nervous system conditions. (1)
Several classes of heterocyclic derivatives have been reported as AR antagonists with high levels of both affinity and selectivity. (2) The [1,2,4]-triazolo[1,5-c]pyrimidine nucleus possesses a low molecular weight and four nitrogen atoms, thus it may be a scaffold with promising pharmacokinetics properties. We have investigated substitutions at the 2, 5 and 8 positions, with the aim of obtaining potent antagonists selective only for one of the four adenosine receptor subtypes. A receptor-driven molecular modeling investigation has been carried out in order to support the experimental binding data and to justify the selectivity against the other receptor subtypes.
(1) Moro, S.; Gao, Z.G.; Jacobson, K.A.; Spalluto, G. Med. Res. Rev. 2006, 26, 131-159.
(2) Muller, C.E.; Jacobson, K.A. Biochim. Biophys. Acta. 2011, 1808, 1290–1308
