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

• Published in: European journal of pharmacology 2001-06, Vol.421 (2), p.85-91
• Main Authors: Mohammadi, Bahram, Haeseler, Gertrud, Leuwer, Martin, Dengler, Reinhard, Krampfl, Klaus, Bufler, Johannes
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Chloride Channels - physiology; Cresols - pharmacology; Dose-Response Relationship, Drug; GABA A receptor; GABA Agents - pharmacology; gamma-Aminobutyric Acid - pharmacology; Humans; Membrane Potentials - drug effects; Phenol - chemistry; Phenol - pharmacology; Phenol derivative; Propofol; Propofol - pharmacology; Rats; Receptors, GABA-A - genetics; Receptors, GABA-A - physiology; Structure-Activity Relationship; Thymol - pharmacology; Xylenes - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01033-0

Propofol directly activates γ-aminobutyric acid (GABA A) receptors in the absence of the natural agonist. This mechanism is supposed to contribute to its sedative–hypnotic actions. We studied the effects of seven structurally related phenol derivatives on chloride inward currents via rat α 1β 2γ 2 GABA A receptors, heterologously expressed in HEK 293 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 phenolic hydroxyl activated chloride currents in the absence of GABA. Concentrations required for half-maximum effect were 980 μM for 2-methylphenol, 230 μM for 2,6-dimethylphenol, 200 μM for thymol, and 23 μM for propofol. Drug-induced chloride currents showed no desensitisation during the 2-s application. These results show that the position of the aliphatic substituents with respect to the phenolic hydroxyl group is the crucial structural feature for direct GABA A activation by phenol derivatives.