HOUSE-FLY HEAD GABA-GATED CHLORIDE CHANNEL - TOXICOLOGICALLY RELEVANT BINDING-SITE FOR AVERMECTINS COUPLED TO SITE FOR ETHYNYLBICYCLOORTHOBENZOATE

[5-3H]Avermectin B1a ([3H]AVM) binds in house fly head membranes to a single saturable, high affinity site (Kd 1.9 nM, Bmax 9.5 pmol/mg protein, 65% specific binding). This radioligand is not displaced by GABA and several noncompetitive blockers of the GABA-gated chloride channel [picrotoxinin, lindane, and 4-n-propyl-4′-ethynylbicycloorthobenzoate (EBOB)]. AVM and 11 analogs thereof including MK-243 and moxidectin vary in IC50s for displacement of [3H]AVM from 26 to 1025 nM and in LD50s to adult female house flies [topical, 24 hr, pretreated with piperonyl butoxide to minimize oxidative detoxification] from 0.01 to 45 μg/g. The IC50 is a good predictor of the LD50 (r = 0.83, n = 11) establishing the toxicological relevance of this [3H]AVM binding assay. These AVM analogs are also noncompetitive displacers of [3H]EBOB binding with EC50 values of 1.7 to 336 nM for the sensitive portion (45-80%) of [3H]EBOB binding. The relative potencies of a series of AVM analogs as inhibitors of [3H]AVM binding correlate well with those for [3H]EBOB binding (r = 0.95, n = 12). It therefore appears that AVM and its analogs (channel openers) act in the GABA-gated chloride channel of house fly head at a site closely coupled to that for EBOB (a channel blocker). © 1992.