Novel classes of CB2 agonists based on 4-oxo-1,4-dihydroquinoline and 4-oxo-1,4-dihydro-1,5-, -1,6- and -1,8-naphthyridine scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over CB1. A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing r(2)ncv=0.84, r(2)cv=0.619, SEE = 0.369, and r(2)pred=0.75. The study provides useful suggestions for the synthesis of new selective analogues with improved affinity.