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-Δ2-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ2-Isoxazolines 3a (3-Br), 6a (3-OMe), 5a (3-Ph), 8a (3-OnPr), and 4a (3-Me) were the ligands with the highest affinity for the α7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 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 6a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6a was found to be the eutomer, with Ki values of 4.6 and 48.7nM against rat and human α7 receptors, respectively. Spirocyclic is better! Significant binding selectivity and functional activity toward α7 nAChR subtypes were achieved with new chiral derivatives, characterized by a Δ2-isoxazoline ring linked to a quinuclidine moiety with a spirocylic junction. The eutomer of the most promising derivative in the series, the 3-O-methoxy analogue (R)-(-)-6, fit well to a model for the α7 nAChRs.
AB - A set of racemic spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ2-Isoxazolines 3a (3-Br), 6a (3-OMe), 5a (3-Ph), 8a (3-OnPr), and 4a (3-Me) were the ligands with the highest affinity for the α7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 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 6a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6a was found to be the eutomer, with Ki values of 4.6 and 48.7nM against rat and human α7 receptors, respectively. Spirocyclic is better! Significant binding selectivity and functional activity toward α7 nAChR subtypes were achieved with new chiral derivatives, characterized by a Δ2-isoxazoline ring linked to a quinuclidine moiety with a spirocylic junction. The eutomer of the most promising derivative in the series, the 3-O-methoxy analogue (R)-(-)-6, fit well to a model for the α7 nAChRs.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1002/cmdc.201000514
DO - 10.1002/cmdc.201000514
M3 - Journal article
C2 - 21365765
SN - 1860-7179
VL - 6
SP - 889
EP - 903
JO - ChemMedChem
JF - ChemMedChem
IS - 5
ER -