Synthesis and alpha4beta2 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 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.
Pallavicini
Marco
M
Istituto di Chimica Farmaceutica e Tossicologica, Università di Milano, viale Abruzzi 42, I-20131 Milano, Italy. marco.pallavincini@unimi.it
Moroni
Barbara
B
Bolchi
Cristiano
C
Clementi
Francesco
F
Fumagalli
Laura
L
Gotti
Cecilia
C
Vailati
Silvia
S
Valoti
Ermanno
E
Villa
Luigi
L
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D007097:Imines / Q000138:chemical synthesis* / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
D007097:Imines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D011392:Proline; C046026:prolinal