Design, Synthesis, and Evaluation of Novel A_2A Adenosine Receptor Agonists

We have been interested in the design, synthesis, and evaluation of novel adenosine A_2A agonists. Through the use of comparative molecular field analysis (CoMFA) we have generated a training model that includes 78 structurally diverse A_2A agonists and correlated their affinity for isolated rat brain receptors with differences in their structural and electrostatic properties. We validated this model by predicting the activity of a test set that included 24 additional A_2A agonists. Our CoMFA model, which incorporates the physiochemical property of dipole and selects against A₁ receptor activity, generated a correlated final model (r² = 0.891) that provides for enhanced A_2A selectivity and predictability. Synthesis, pharmacological evaluation, and modeling of four novel ligands further validate the utility and predictive power (r² = 0.626) of the CoMFA model.