A number of propofol (2,6-diisopropylphenol) congeners and derivatives were synthesized and their in vitro capability to affect GABAA receptors determined by the inhibition of the specific [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to rat whole brain membranes. Introduction of halogen (Cl, Br, and I) and benzoyl substituents in the para position of the phenyl group resulted in ligands with higher potency at inhibiting [35S]TBPS binding. A quantitative structure-affinity relationship (QSAR) study demonstrated that affinity is enhanced by increases in lipophilicity of the ligand whereas affinity is adversely affected by increases in size of the substituent para to the phenolic hydroxyl group. Consistent with the displacement of [35S]TBPS and with the activation of GABAA receptors, we demonstrate that ligands displaying high affinity (i.e., 2-4, and 8) are able to increase GABA-stimulated chloride currents in oocytes expressing human GABAA receptors and to directly activate chloride currents in an electrophysiological assay. Among them, compound 4 showed a rather peculiar profile in the electrophysiological examination with cloned alpha1beta2gamma2 GABAA receptors. Indeed, compared to propofol, it displayed a much greater efficacy at potentiating GABA-elicited chloride currents, but a much lower efficacy at producing a direct activation of the chloride channel in the absence of GABA. This behavior may give to compound 4 pharmacological properties that are more similar to anxiolytic and anticonvulsant drugs than to those of general anesthetics.