Applied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor. A unique pharmacophore model was derived which involves six critical zones: (a) a pi-electron rich aromatic (PAR) zone; (b) two electron-rich zones delta 1 and delta 2 placed at 5.0 and 4.5 A respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR). The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the delta 1 zone, accounts for R and S differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.