Novel and potent 6-chloro-3-pyridinyl ligands for the alpha4beta2 neuronal nicotinic acetylcholine receptor.
1-[(6-Chloro-3-pyridinyl)methyl]-2-imidazolidine (1), the N-desnitro metabolite of the major insecticide imidacloprid, is known to have similar potency to that of (-)-nicotine as an inhibitor of [3H](-)-nicotine binding at the rat recombinant alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR); IC50 values in the present study are 3.8 nM for (-)-nicotine, 6.0 nM for 1, and 155 nM for imidacloprid. Synthesis of new analogues of 1, modified only in the heterocyclic moiety (five-, six-, or seven-membered rings with NH, S, O, and CH2 substituents), gave compounds varying from 4-fold higher potency (2-iminothiazole analogue 10) to >6000-fold less active than (-)-nicotine. Other potent N-[(6-chloro-3-pyridinyl)methyl] compounds are those in which the heterocyclic imine is replaced with pyrrolidine (19) (IC50 9 nM) or trimethylammonium (22) (IC50 18 nM). A novel conversion of (-)-nicotine to its 6-chloro analogue increased the potency 2-fold. These 6-chloro-3-pyridinyl compounds are of interest as novel nAChR probes and potential metabolites of candidate insecticides.
Latli
B
B
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, 114 Wellman Hall, University of California, Berkeley, California 94720-3112, USA.
D'Amour
K
K
Casida
J E
JE
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D007313:Insecta / Q000166:cytology; D007306:Insecticides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009474:Neurons / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D007306:Insecticides; D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins