Synthesis and α4β2 nicotinic affinity of 2-pyrrolidinylmethoxyimines and prolinal oxime ethers

Homochiral E and Z isomers of N-methylprolinal O-isopropyloxime and (1-methyl-2-pyrrolidinyl)methoxyimines were synthesized as candidate bioisosteres of nicotine and its isoxazolic analogue ABT 418. Two of them, namely (S)-2-isopropylideneaminooxymethyl- and (Z)-(S)-2-ethylideneaminooxymethyl-1-methylpyrrolidine, proved to bind at α4β2 nicotinic acetylcholine receptor with submicromolar affinity and remarkable selectivity over α7 and muscarinic receptors thus supporting the hypothesized bioisosteric relationship between their methyloxyimino group and the aromatic heterocycles of the reference ligands.