THE ACTIONS OF ORALLY ACTIVE GABA(B) RECEPTOR ANTAGONISTS ON GABAERGIC TRANSMISSION INVIVO AND INVITRO

The goal of this report is to present the results obtained with three new GABA(B) receptor antagonists. CGP 54062 has an IC50 in a GABA(B) binding test of 0.013 muM which is roughly 2500-fold lower than one of the most potent blockers known so far, CGP 35348 (IC50 = 34 muM). CGP 46381 and CGP 36742 have IC50s of 4.9 and 36 muM respectively. The latter two compounds are the first orally active GABA(B) receptor antagonists. All three compounds bind to the GABA(B) receptor selectively, and are inactive in a number of binding tests assessing the compounds' affinity to various other receptor sites. The effect of these blockers on GABAergic transmission was investigated in the CA1 area of hippocampal slices. The Schaffer collateral/commissural fibers were stimulated and the evoked postsynaptic potentials were recorded intracellularly in pyramidal neurons. The three antagonists blocked the late inhibitory postsynaptic potential with the following rank order of potency CGP 54062 > 46381 > 36742 approximately 35348. These findings support the hypothesis that these potentials are mediated by GABA(B) receptors. Orally administered CGP 36742 and CGP 46381 block the neuronal depression induced by iontophoretically applied baclofen in anaesthetised rats. Up to a dose of 10 mg/kg iv. CGP 54062 was inactive and thus does not appear to cross the blood-brain barrier at this dose. In anaesthetised rats the effects of the three new GABA(B) antagonists and of CGP 35348 were investigated on the paired-pulse inhibition of the population spikes evoked in the CA1 area of the hippocampus. In this classical test, which assesses GABAergic transmission, CGP 35348, 46381 and 36742 dose dependently attenuated paired-pulse inhibition measured at latencies of > 100 ms. These findings suggest that GABA(B) antagonists attenuate the late phase of GABA transmission in the hippocampus in vivo.