5-Azidoimidacloprid and an acyclic analogue as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors.
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.
Kagabu
S
S
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Maienfisch
P
P
Zhang
A
A
Granda-Minones
J
J
Haettenschwiler
J
J
Kayser
H
H
Maetzke
T
T
Casida
J E
JE
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
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