| Popis: |
Seven avermectin analogues that exhibited a wide range of anthelminthic and insecticidal activities were evaluated for their effects on γ-aminobutyric acid (GABA)-sensitive and GABA-insensitive components of chloride transport across mouse brain vesicle membranes. All of the compounds except the biologically inactive octahydro analogue of abamectin inhibited GABA-dependent chloride uptake into brain vesicles. The relative inhibitory potencies of the six active analogues varied over a more than 60-fold range and were generally correlated with their potencies as invertebrate toxicants. These six compounds, but not the octahydro analogue, also stimulated GABA-insensitive chloride efflux from preloaded brain vesicles. In this assay, the potencies of the six active compounds varied over a 6-fold range and were not correlated with potencies for the inhibition of GABA-dependent chloride uptake. Moreover, neither potencies nor relative efficacies for the stimulation of chloride efflux were obviously correlated with biological activity against invertebrates. These data show that avermectins are capable of modifying chloride permeability in mouse brain vesicle preparations by two distinct mechanisms, one involving GABA receptors and a second involving one or more additional chloride ionophores unrelated to GABA receptors. Both actions may contribute to the signs of intoxication observed for abamectin and other avermectins in mammals. |
