EXPRESSION AND PROPERTIES OF RECOMBINANT ALPHA(1)BETA(2)GAMMA(2) AND ALPHA(5)BETA(2)GAMMA(2) FORMS OF THE RAT GABA-A RECEPTOR

The interaction of omega (benzodiazepine) modulatory drugs with transiently expressed alpha1beta2gamma2 and alpha5beta2gamma2 forms of the rat GABA(A) receptor was investigated using [H-3]flumazenil as a probe in in vitro radioligand binding assays. The imidazopyridines alpidem and zolpidem exhibited pronounced selectivity for the alpha1- compared to the alpha5-containing construct, whereas omega (benzodiazepine) site modulatory compounds from other chemical series including diazepam, tetrazepam, zopiclone, triazolam, bretazenil and midazolam behaved as relatively non-selective drugs. In the presence of 10 muM gamma-aminobutyric acid (GABA) the potencies of diazepam, flunitrazepam and midazolam to inhibit [H-3]flumazenil binding to the alpha1-construct were increased 3 to 5 fold, whereas with 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate methyl ester a 2.5-fold reduction in potency was observed. Similar modulatory effects of GABA were obtained with these drugs, using the alpha5-construct. We suggest that these GABA shift determinations of [H-3]flumazenil binding can be used as a rapid test to evaluate the intrinsic activities of omega modulatory compounds.