Novel and Potent 6-Chloro-3-pyridinyl Ligands for the α4β2 Neuronal Nicotinic Acetylcholine Receptor

Abstract

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.

Exploring the Nature of Molecular Recognition in Nicotinic Acetylcholine Receptors

“…Abbott researchers, in one of numerous significant contributions to this field describe a series of racemic alkaloids aimed at probing the suitability of substituted aromatics [c99-118] as replacements for nicotine's 3-pyridyl moiety [156]. Methylation of c99 to the nicotine isostere c100, results in a 20-fold increase in α4β2 affinity, similar to the effect seen when other pyrrolidine-based nicotinic ligands are methylated.…”

Agonists at the a4b2 Nicotinic Acetylcholine Receptors Relationships and Molecular Modelling

“…Since then, some new and interesting compounds (i.e., epiboxidine [6], UB-165 [7], the imidacloprid analogues [8,9], and the quinuclidine compounds [10,11]) have appeared providing further knowledge of the nicotinic pharmacophore and thereby made it possible to discuss the structure-activity relationships (SAR) throughout the compound series. In this review, only compounds acting on the α4β2 nAChRs are discussed, as the structural demands for ligands acting at the various subtypes are somewhat differing.…”

Crystal Structure of 8-(6-Chloro-pyridin-3-ylmethyl)-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,6-chloropyridyl-3-yl-4] triazin-3-one

“…1 Neonicotinoidsareasetofnicotine-basedinsecticide that include the chemicals imidacloprid, clothianidin, acetamiprid, thiacloprid, thiamethoxam, dinotefuran and nitenpyram; they possess either nitromethylene, nitroimine or cyanoimine groups. 2,3 The neonicotinoids has close affinity towardsinsectnAChRs,whichsuggeststhatnAChRsarelikely to represent the principal site of action of these compounds.…”