title: Interaction of dinotefuran and its analogues with nicotinic acetylcholine receptors of cockroach nerve cords.
abstract: To investigate the action of dinotefuran (MTI-446, 1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine), a recently developed insecticide, on insect nicotinic acetylcholine receptors (nAChRs), we determined the potencies of the compound and 15 analogues in inhibiting the specific binding of [3H]epibatidine (EPI), a nAChR agonist, and [3H]alpha-bungarotoxin (alpha-BGT), a competitive nAChR antagonist, to the nerve cord membranes of American cockroaches (Periplaneta americana). Racemic dinotefuran inhibited [3H]EPI binding with an IC50 of 890 nM and [3H]alpha-BGT binding with an IC50 of 36.1 microM. Scatchard analysis indicated that the dinotefuran inhibition of [3H]EPI binding was a competitive one. Slight structural modification caused a drastic reduction in potency; only four analogues were found to be equipotent to or more potent than dinotefuran. Chloropyridinyl and chlorothiazolyl neonicotinoid insecticides displayed two or three orders of magnitude higher potency than dinotefuran. There was a good correlation between the IC50 values of tested compounds obtained with [3H]EPI and those obtained with [3H]alpha-BGT. A better correlation was observed between 3-h knockdown activities (KD50) against German cockroaches (Blattella germanica) and IC50 values obtained from [3H]EPI assays than between 24-h lethal activities (LD50) and IC50 values. While the results indicate that dinotefuran and its analogues interact with the ACh-binding site in cockroach nAChRs, it remains to be elucidated why they displayed lower potencies than those expected based on their insecticidal activities.
authors.affiliation: Department of Life Science and Biotechnology, Shimane University, Matsue, Shimane 690-8504, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Mori
authors.forename: Takashi
authors.initials: T
authors.lastname: Okumoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kawahara
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ozoe
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002038:Bungarotoxins / Q000378:metabolism; D003058:Cockroaches / Q000187:drug effects* / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D000073943:Neonicotinoids; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D006146:Guanidines; D007306:Insecticides; D000073943:Neonicotinoids; D009574:Nitro Compounds; D011725:Pyridines; D011978:Receptors, Nicotinic; D014316:Tritium; C465368:dinotefuran; C082748:epibatidine