3D-QSAR studies comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 26 structurally diverse subcutaneous pentylenetetrazol (scPTZ) active enaminone analogues, previously synthesized in our laboratory. CoMFA and CoMSIA were employed to generate models to define the specific structural and electrostatic features essential for enhanced binding to the putative GABA receptor. The 3D-QSAR models demonstrated a reliable ability to predict the CLogP of the active anticonvulsant enaminones, resulting in a q(2) of 0.558 for CoMFA, and a q(2) of 0.698 for CoMSIA. The outcomes of the contour maps for both models provide detailed insight for the structural design of novel enaminone derivatives as potential anticonvulsant agents.