Design, synthesis, and evaluation of novel A(2A) adenosine receptor agonists

We have been interested in the design, synthesis, and evaluation of novel a denosine A(2A) agonists. Through the use of comparative molecular field ana lysis (CoMFA) we have generated a training model that includes 78 structura lly diverse A(2A) agonists and correlated their affinity for isolated rat b rain receptors with differences in their structural and electrostatic prope rties. We validated this model by predicting the activity of a test set tha t included 24 additional A(2A) agonists. Our CoMFA model, which incorporate s the physiochemical property of dipole and selects against A(1) receptor a ctivity, generated a correlated final model (r(2) = 0.891) that provides fo r enhanced A(2A) selectivity and predictability. Synthesis, pharmacological evaluation, and modeling of four novel ligands further validate the utilit y and predictive power (r(2) = 0.626) of the CoMFA model.