Activity of chlormethiazole at human recombinant GABA A and NMDA receptors

Investigation into the modulatory effects of chlormethiazole at human recombinant γ ‐aminobutyric acid A receptor (GABA A ) and N ‐methyl‐ D ‐aspartate (NMDA) receptors was undertaken to gain insight into its mechanism of action and determine if the drug exhibited any subtype‐selective activity. Despite a structural similarity to the β ‐subunit‐selective compound loreclezole, chlormethiazole did not show any difference in maximum efficacy and only a slight difference in EC 50 in its potentiating action at α 1 β 1 γ 2 and α 1 β 2 γ 2 GABA A receptor subtypes with preference for α 1 β 1 γ 2. Similar to the previously reported subtype‐dependent activity of pentobarbital, chlormethiazole elicited a significantly greater degree of maximum potentiation on receptors lacking a γ 2 subunit, and also those receptors containing an α 4 or α 6 subunit. This also demonstrates that chlormethiazole does not act via the benzodiazepine binding site. Unlike pentobarbital and propofol, chlormethiazole elicited only a slight direct GABA A receptor activation at concentrations up to 1 m M . In addition, the drug did not potentiate anaesthetic‐mediated currents elicited by pentobarbital or propofol, suggesting that chlormethiazole may be acting via an anaesthetic binding site. Chlormethiazole produced weak nonselective inhibition of human NMDA NR1a+NR2A and NR1a+NR2B receptors. IC 50 's were approximately 500 μ M that likely exceed the therapeutic dose range for chlormethiazole, indicating that the primary mechanism of the compounds in vivo activity is via GABA A receptors.British Journal of Pharmacology (2003) 140 , 1045–1050. doi: 10.1038/sj.bjp.0705540