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Design, Synthesis, and Pharmacological Characterization of Novel Spirocyclic Quinuclidinyl‐Δ 2 ‐Isoxazoline Derivatives as Potent and Selective Agonists of α7 Nicotinic Acetylcholine Receptors
Author(s) -
Dallanoce Clelia,
Magrone Pietro,
Matera Carlo,
Frigerio Fabio,
Grazioso Giovanni,
De Amici Marco,
Fucile Sergio,
Piccari Vanessa,
Frydenvang Karla,
Pucci Luca,
Gotti Cecilia,
Clementi Francesco,
De Micheli Carlo
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000514
Subject(s) - homomeric , chemistry , enantiomer , acetylcholine receptor , nicotinic agonist , stereochemistry , receptor , selectivity , stereoselectivity , potency , in vitro , biochemistry , protein subunit , gene , catalysis
A set of racemic spirocyclic quinuclidinyl‐Δ 2 ‐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. Δ 2 ‐Isoxazolines 3 a (3‐Br), 6 a (3‐OMe), 5 a (3‐Ph), 8 a (3‐O n Pr), and 4 a (3‐Me) were the ligands with the highest affinity for the α7 subtype ( K i values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 n M , 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 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 n M against rat and human α7 receptors, respectively.