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-c hloropyridin-3-ylmethy)-2-nitroiminoimidazolidine (1), and an acyclic analo gue, N-(5-azido-6-chloropyridin-3-ylmethyl)-N'-methyl-N " -nitroguanidine ( 2), were prepared in good yields as candidate photoaffinity probes for mamm alian and insect nicotinic acetylcholine receptors (nAChRs). The essential intermediate was 5-azido-6-chloropyridin-3-ylmethyl chloride (3) prepared i n two: ways: from, 6-chloro-5-nitronicotinic acid by selective reduction an d 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 achiev ed in good,yields via the hexahydrotriazine intermediate 14. Fortuitously, the azido substituent in land 2 increases' the affinity 7-79-fold for rat b rain and recombinant (alpha4 beta2 nAChRs:(K(i)s 4.4-60 nM competing with [ H-3](-)-nicotine) while maintaining high potency on both insect nAChRs (Dro sophila and Myzus) (K(i)s 1-5 nM competing with [H-3]imidacloprid). Azidopy ridinyl compounds 1 and 2 are therefore candidate photoaffinity probes for characterization. of both mammalian and insect receptors.