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-nitroiminoimidazolidine (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 α4β2 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.