NOVEL AZOLE DERIVATIVES ARE ANTAGONISTS AT THE INHIBITORY GABA RECEPTOR ON THE SOMATIC MUSCLE-CELLS OF THE PARASITIC NEMATODE ASCARIS-SUUM

The somatic muscle cells of the parasitic nematode Ascaris suum posses s GABA receptors that gate chloride conductances in a similar fashion to the mammalian GABA, receptor subtype. These receptors mediate muscl e relaxation and are the site of action of the anthelmintic piperazine . The properties of this receptor differ from the properties of the GA BA-gated chloride receptors in the mammalian host, in particular they are not as sensitive to mammalian GABA receptor antagonists such as bi cuculline and picrotoxin. Using two-electrode intracellular electrophy siological recording techniques from Ascaris muscle cells, we have tes ted the potency of a series of azole derivatives for their ability to block the chloride-dependent GABA response. The lead compound, SN60607 8, 6-dichloro-4-trifluromethylphenyl)-4-(4,5-dicyano- 1H-imidazol-2-yl )-2H-1,2,3-triazole, and 4 structurally related compounds reversibly b locked the conductance increase elicited by 30 mu M GABA with IC(50)s of less than 10 mu M. SN606078 (10 mu M) decreased the slope of the do se-response curve for GABA, suggesting a non-competitive mechanism of action. In two-electrode voltage clamp experiments, 10 mu M SN606078 b locked the outward current elicited by 20 mu M GABA in a voltage-depen dent manner with 72 +/- 2% inhibition at -20 mV and 49 +/- 6% inhibiti on at -40 mV. These observations indicate that SN606078 may act as an open-channel blocker of the GABA-gated chloride channel in A. suum.