Bioorganic & Medicinal Chemistry Letters 2004-12-06

Synthesis and alpha4beta2 nicotinic affinity of 2-pyrrolidinylmethoxyimines and prolinal oxime ethers.

Marco Pallavicini, Barbara Moroni, Cristiano Bolchi, Francesco Clementi, Laura Fumagalli, Cecilia Gotti, Silvia Vailati, Ermanno Valoti, Luigi Villa

Index: Bioorg. Med. Chem. Lett. 14(23) , 5827-30, (2004)

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Abstract

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 alpha4beta2 nicotinic acetylcholine receptor with submicromolar affinity and remarkable selectivity over alpha7 and muscarinic receptors thus supporting the hypothesized bioisosteric relationship between their methyloxyimino group and the aromatic heterocycles of the reference ligands.