Structural requirements of phenol derivatives for direct activation of chloride currents via GABA(A) receptors

Propofol directly activates gamma -aminobutyric acid (GABA(A)) receptors in the absence of the natural agonist. This mechanism is supposed to contribu te to its sedative-hypnotic actions. We studied the effects of seven struct urally related phenol derivatives on chloride inward currents via rat alpha (1)beta (2)gamma (2) GABA(A) receptors, heterologously expressed in HEK 29 3 cells in order to find structural determinants for this direct agonistic action. Only compounds with the phenolic hydroxyl attached directly to the benzene ring and with aliphatic substituents in ortho position to the pheno lic hydroxyl activated chloride currents in the absence of GABA. Concentrat ions required for half-maximum effect were 980 muM for 2-methylphenol, 230 muM for 2,6-dimethylphenol, 200 muM for thymol, and 23 muM for propofol. Dr ug-induced chloride currents showed no desensitisation during the 2-s appli cation. These results show that the position of the aliphatic substituents with respect to the phenolic hydroxyl group is the crucial structural featu re for direct GABA(A) activation by phenol derivatives. (C) 2001 Elsevier S cience B.V. All rights reserved.