title: 5-Azidoimidacloprid and an acyclic analogue as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors.
abstract: The 5-azido analogue of the major insecticide imidacloprid, 1-(5-azido-6-chloropyridin-3-ylmethyl)-2-nitroiminoimidaz olidine (1), and an acyclic analogue, N-(5-azido-6-chloropyridin-3-ylmethyl)-N'-methyl-N' '-nitroguanidine (2), were prepared in good yields as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors (nAChRs). The essential intermediate was 5-azido-6-chloropyridin-3-ylmethyl chloride (3) prepared in two ways: from 6-chloro-5-nitronicotinic acid by selective reduction and then diazotization, and from N-(6-chloropyridin-3-ylmethyl)morpholine by an electrophilic azide introduction with lithium diisopropylamide followed by chlorine substitution of morpholine with ethyl chloroformate. Coupling of 3 with 2-nitroiminoimidazolidine gave 1. Conversion of 3 to 2 was achieved in good yields via the hexahydrotriazine intermediate 14. Fortuitously, the azido substituent in 1 and 2 increases the affinity 7-79-fold for rat brain and recombinant alpha4beta2 nAChRs (K(i)s 4.4-60 nM competing with [(3)H](-)-nicotine) while maintaining high potency on both insect nAChRs (Drosophila and Myzus) (K(i)s 1-15 nM competing with [(3)H]imidacloprid). Azidopyridinyl compounds 1 and 2 are therefore candidate photoaffinity probes for characterization of both mammalian and insect receptors.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kagabu
authors.forename: P
authors.initials: P
authors.lastname: Maienfisch
authors.forename: A
authors.initials: A
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Granda-Minones
authors.forename: J
authors.initials: J
authors.lastname: Haettenschwiler
authors.forename: H
authors.initials: H
authors.lastname: Kayser
authors.forename: T
authors.initials: T
authors.lastname: Maetzke
authors.forename: J E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D001042:Aphids; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004331:Drosophila melanogaster; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D048289:Imidazolidines; D066298:In Vitro Techniques; D008566:Membranes; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C419157:1-(5-azido-6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine; D001386:Azides; D006146:Guanidines; D007093:Imidazoles; D048289:Imidazolidines; C419158:N-(5-azido-6-chloropyridin-3-ylmethyl)-N'-methyl-N''-nitroguanidine; D019920:Photoaffinity Labels; D011725:Pyridines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins