TY - JOUR
T1 - Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Delta2 -isoxazoline derivatives as potent and selective agonists of alpha7 nicotinic acetylcholine receptors
AU - Dallanoce, Clelia
AU - Magrone, Pietro
AU - Matera, Carlo
AU - Frigerio, Fabio
AU - Grazioso, Giovanni
AU - De Amici, Marco
AU - Fucile, Sergio
AU - Piccari, Vanessa
AU - Frydenvang, Karla Andrea
AU - Pucci, Luca
AU - Gotti, Cecilia
AU - Clementi, Francesco
AU - De Micheli, Carlo
N1 - Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2011/5/2
Y1 - 2011/5/2
N2 - A set of racemic spirocyclic quinuclidinyl-¿(2) -isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (a7) and heteromeric (a4ß2) nicotinic acetylcholine receptors. ¿(2) -Isoxazolines 3¿a (3-Br), 6¿a (3-OMe), 5¿a (3-Ph), 8¿a (3-OnPr), and 4¿a (3-Me) were the ligands with the highest affinity for the a7 subtype (K(i) values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 nM, respectively), and showed excellent a7 versus a4ß2 subtype selectivity. These compounds, tested in electrophysiological experiments against human a7 and a4ß2 receptors stably expressed in cell lines, behaved as partial a7 agonists with varying levels of potency. The two enantiomers of (±)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate 6¿a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6¿a was found to be the eutomer, with K(i) values of 4.6 and 48.7 nM against rat and human a7 receptors, respectively.
AB - A set of racemic spirocyclic quinuclidinyl-¿(2) -isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (a7) and heteromeric (a4ß2) nicotinic acetylcholine receptors. ¿(2) -Isoxazolines 3¿a (3-Br), 6¿a (3-OMe), 5¿a (3-Ph), 8¿a (3-OnPr), and 4¿a (3-Me) were the ligands with the highest affinity for the a7 subtype (K(i) values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 nM, respectively), and showed excellent a7 versus a4ß2 subtype selectivity. These compounds, tested in electrophysiological experiments against human a7 and a4ß2 receptors stably expressed in cell lines, behaved as partial a7 agonists with varying levels of potency. The two enantiomers of (±)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate 6¿a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6¿a was found to be the eutomer, with K(i) values of 4.6 and 48.7 nM against rat and human a7 receptors, respectively.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1002/cmdc.201000514
DO - 10.1002/cmdc.201000514
M3 - Journal article
C2 - 21365765
VL - 6
SP - 889
EP - 903
JO - Farmaco
JF - Farmaco
SN - 1860-7179
IS - 5
ER -