title: Insect muscarinic acetylcholine receptor: pharmacological and toxicological profiles of antagonists and agonists.
abstract: The insect muscarinic acetylcholine receptor (mAChR) is evaluated as a potential target for insecticide action. The mammalian M2/M4-selective antagonist radioligand [3H]AF-DX 384 (a pirenzepine analogue) binds to Drosophila mAChR at a single high-affinity site identical to that for the nonselective antagonist [3H]quinuclidinyl benzilate (QNB) and with a pharmacological profile distinct from that of all mammalian mAChR subtypes. Three nonselective antagonists (QNB, scopolamine, and atropine) show the highest affinity (Ki=0.5-2.4 nM) at the Drosophila target, and AF-DX 384 and M3-selective 4-DAMP (dimethyl-4-(diphenylacetoxy)piperidinium iodide) rank next in potency (Ki=5-18 nM). Eleven muscarinic antagonists generally exhibit higher affinity than eight agonists. On injection into houseflies, the antagonists 4-DAMP and (S)-(+)-dimethindene produce suppressed movement, the agonist (methyloxadiazolyl)quinuclidine causes knockdown and tremors, and all of them inhibit [3H]QNB binding ex vivo, indicating possible mAChR-mediated intoxication. The insect mAChR warrants continuing study in lead generation to discover novel insecticides.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
authors.forename: Hideo
authors.initials: H
authors.lastname: Honda
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tomizawa
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D006793:Houseflies / Q000378:metabolism; D007313:Insecta / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000494:pharmacology* / Q000633:toxicity; D018727:Muscarinic Antagonists / Q000494:pharmacology* / Q000633:toxicity; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium
chemical_list: D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D014316:Tritium; C065959:AFDX 384; D010890:Pirenzepine; D011813:Quinuclidinyl Benzilate