The ionotropic glutamate NMDA/NR2B receptor and its interaction with ifenprodil-like noncompetitive ligands were investigated by a combined ligand-based and target-based approach. First, we generated 3D pharmacophore hypotheses and identified common chemical features that are shared by a training set of well-known NR2B antagonists. The binding mode of the most representative ligand was also studied by molecular docking. Because the docking results and the suggested 3D pharmacophore model were in good agreement, we obtained new information about the NR2B ifenprodil site. The best pharmacophoric hypothesis was used as a query for in silico screening; this allowed the identification of new "hit". We synthesized "hit-compound" analogues, and some of the molecules showed significant activity both in binding and functional assay as well as in vivo anticonvulsant efficacy in DBA/2 mice. The most active derivatives also exhibited neuroprotective effects against glutamate-induced toxicity in HCN-1A cells.