An approach for binding affinity evaluation is suggested and exemplified using a set of triazolo [1,5-a] quinoxaline for the (R, S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid (AMPA) receptor. Biological activity toward the AMPA receptor (expressed as -log IC50) was taken as a dependent variable for building Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) models. The resulting models show the ways of increasing the binding affinity to the AMPA receptor as a potential target for epilepsy. The statistically significant results show that the cross-validated r2CV value (0.766) for the CoMFA model is greater than (0.758) for the CoMSIA model. The non-cross validated run giving the coefficient of determination r2 values of 0.944 and 0.919 for CoMFA and CoMSIA, respectively, provided good correlation between the observed and computed affinities of the training set compounds. The resulting CoMFA and CoMSIA models indicate that steric, electrostatic, hydrophobic (lipophilic), hydrogen bond donor and acceptor substituents play a significant role in increasing the binding affinity and selectivity of the compounds toward the AMPA receptor.