Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors

Clelia Dallanoce, Pietro Magrone, Carlo Matera, Fabio Frigerio, Giovanni Grazioso, Marco DeAmici, Sergio Fucile, Vanessa Piccari, Karla Frydenvang, Luca Pucci, Cecilia Gotti, Francesco Clementi, Carlo DeMicheli

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)889-903
Number of pages15
JournalChemMedChem
Volume6
Issue number5
DOIs
Publication statusPublished - May 2 2011

Keywords

  • Δ-isoxazoline derivatives
  • α7 agonists
  • Electrophysiological assays
  • Neuronal nicotinic acetylcholine receptors
  • X-ray crystallography

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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  • Cite this

    Dallanoce, C., Magrone, P., Matera, C., Frigerio, F., Grazioso, G., DeAmici, M., Fucile, S., Piccari, V., Frydenvang, K., Pucci, L., Gotti, C., Clementi, F., & DeMicheli, C. (2011). Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors. ChemMedChem, 6(5), 889-903. https://doi.org/10.1002/cmdc.201000514