PROPOFOL ANALOGS - SYNTHESIS, RELATIONSHIPS BETWEEN STRUCTURE AND AFFINITY AT GABA(A) RECEPTOR IN RAT-BRAIN, AND DIFFERENTIAL ELECTROPHYSIOLOGICAL PROFILE AT RECOMBINANT HUMAN GABA(A) RECEPTORS

A number of propofol (2,6-diisopropylphenol) congeners and derivatives were synthesized and their in vitro capability to affect GABA(A) rece ptors determined by the inhibition of the specific [S-35]-tert-butylbi cyclophosphorothionate ([S-35]TBPS) binding to rat whole brain membran es. Introduction of halogen (Cl, Br, and I) and benzoyl substituents i n the para position of the phenyl group resulted in ligands with highe r potency at inhibiting [S-35]TBPS binding. A quantitative structure-a ffinity relationship (QSAR) study demonstrated that affinity is enhanc ed by increases in lipophilicity of the ligand whereas affinity is adv ersely affected by increases in size of the substituent para to the ph enolic hydroxyl group. Consistent with the displacement of [S-35]TBPS and with the activation of GABA(A) receptors, we demonstrate that liga nds displaying high affinity (i.e., 2-4, and 8) are able to increase G ABA-stimulated chloride currents in oocytes expressing human GABA(A) r eceptors and to directly activate chloride currents in an electrophysi ological assay. Among them, compound 4 showed a rather peculiar profil e in the electrophysiological examination with cloned alpha(1) beta(2) gamma(2) GABA(A) receptors. Indeed, compared to propofol, it displaye d a much greater efficacy at potentiating GABA-elicited chloride curre nts, but a much lower efficacy at producing a direct activation of the chloride channel in the absence of GABA. This behavior may give to co mpound 4 pharmacological properties that are more similar to anxiolyti c and anticonvulsant drugs than to those of general anesthetics.