Structural features of azidopyridinyl neonicotinoid probes conferring high affinity and selectivity for mammalian alpha4beta2 and Drosophila nicotinic receptors.
The higher toxicity of neonicotinoid insecticides such as N-(6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine (imidacloprid) to insects than mammals is due in large part to target site specificity at the corresponding nicotinic acetylcholine receptors (nAChRs). We propose that neonicotinoids with a protonated N-unsubstituted imine or equivalent substituent recognize the anionic subsite of the mammalian alpha4beta2 nAChR whereas the negatively charged (delta(-)) tip of the neonicotinoid insecticides interacts with a putative cationic subsite of the insect nAChR. This hypothesis can be tested by using two photoaffinity probes that differ only in the N-unsubstituted imine vs negatively charged (delta(-)) tip. Synthesis methodology was developed for compounds combining three moieties: pyridin-3-ylmethyl or 6-chloropyridin-3-ylmethyl and their 4- and 5-azido analogues; imidazolidine, 4-imidazoline or 4-thiazoline; and N-unsubstituted imine, nitroimine, cyanoimine, or nitromethylene. Structure-activity studies compared displacement of [(3)H]nicotine binding in mammalian alpha4beta2 nAChR and [(3)H]imidacloprid binding in Drosophila nAChR. Preferred compounds are N-(5-azido-6-chloropyridin-3-ylmethyl) with 2-iminothiazoline for alpha4beta2 (K(i) = 0.47 nM) and with 2-nitroiminothiazoline or 2-nitromethyleneimidazolidine for Drosophila (K(i) = 0.72-3.9 nM).
Zhang
Nanjing
N
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, USA.
Tomizawa
Motohiro
M
Casida
John E
JE
D000818:Animals; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D004330:Drosophila; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007306:Insecticides / Q000378:metabolism; D051379:Mice; D000073943:Neonicotinoids; D009574:Nitro Compounds; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001386:Azides; D007093:Imidazoles; D007097:Imines; D007306:Insecticides; D000073943:Neonicotinoids; D009574:Nitro Compounds; D019920:Photoaffinity Labels; D011725:Pyridines; D011978:Receptors, Nicotinic; D013844:Thiazoles; C403531:nicotinic receptor alpha4beta2; C082359:imidacloprid