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 possess GABA receptors that gate chloride conductances in a similar fashion to the mammalian GABAA receptor subtype. These receptors mediate muscle relaxation and are the site of action of the anthelmintic piperazine. The properties of this receptor differ from the properties of the GABA-gated chloride receptors in the mammalian host, in particular they are not as sensitive to mammalian GABA receptor antagonists such as bicuculline and picrotoxin. Using two-electrode intracellular electrophysiological recording techniques from Ascaris muscle cells, we have tested the potency of a series of azole derivatives for their ability to block the chloride-dependent GABA response. The lead compound, SN606078, 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(4,5-dicyano-1H-imidazo l-2-yl)-2H- 1,2,3-triazole, and 4 structurally related compounds reversibly blocked the conductance increase elicited by 30 microM GABA with IC50s of less than 10 microM. SN606078 (10 microM) decreased the slope of the dose-response curve for GABA, suggesting a non-competitive mechanism of action. In two-electrode voltage clamp experiments, 10 microM SN606078 blocked the outward current elicited by 20 microM GABA in a voltage-dependent manner with 72 +/- 2% inhibition at -20 mV and 49 +/- 6% inhibition at -40 mV. These observations indicate that SN606078 may act as an open-channel blocker of the GABA-gated chloride channel in A. suum.
Bascal
Z
Z
Department of Physiology and Pharmacology, University of Southampton.
Holden-Dye
L
L
Willis
R J
RJ
Smith
S W
SW
Walker
R J
RJ
D000818:Animals; D017165:Ascaris suum / Q000502:physiology*; D001393:Azoles / Q000494:pharmacology*; D002712:Chlorides / Q000502:physiology; D004553:Electric Conductivity; D018756:GABA Antagonists / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009132:Muscles / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D018079:Receptors, GABA / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001393:Azoles; D002712:Chlorides; D018756:GABA Antagonists; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid