Anthelmintic actions on homomer-forming nicotinic acetylcholine receptor subunits:: chicken α7 and ACR-16 from the nematode Caenorhabditis elegans

Two homomer-forming nicotinic acetylcholine receptor subunits with 47% identity in their amino acid sequences were employed to compare the actions of cholinergic anthelmintics and ivermectin on expressed vertebrate and nematode nicotinic receptors of known molecular composition. Voltage-clamp electrophysiology was used to study recombinant nicotinic receptors expressed in Xenopus laevis oocytes following nuclear injection of cDNA encoding either chicken alpha7 or Caenorhabditis elegans ACR-16 (Ce21) subunits, Butamisole, morantel and metyridine were without agonist actions on either alpha7 or ACR-16 nicotinic receptors in the range 10 nM-1 mM. However, butamisole (pIC(50) = 4.9 for both alpha7 and ACR-16) and morantel (PIC50 = 5.6 for alpha7 and 5.7 for ACR-16) antagonized responses of both alpha7 and ACR-16 receptors to acetylcholine. Metyridine (1 mM) did not affect responses to acetylcholine of either receptor. Oxantel was without agonist actions on ACR-16, but was an acetylcholine antagonist (pIC(50) = 5.4). In contrast, it was found to have low efficacy agonist action (pEC(50) = 4.4) on alpha7 at concentrations in the range 10-300 muM. In agreement with a previous study, ivermectin (30 muM), an agonist of L-glutamate-gated chloride channels, enhanced the amplitude of responses to acetylcholine of alpha7 nicotinic receptors. However, this same concentration of ivermectin (30 muM) did not potentiate the acetylcholine-induced responses of ACR-16, but rather resulted in a slight attenuation. We conclude that oxantel and ivermectin have identified new pharmacological differences between the chicken alpha7 nicotinic receptor and its C. elegans homologue ACR-16. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.