New spirocyclic Δ2-isoxazoline derivatives related to selective agonists of α7 neuronal nicotinic acetylcholine receptors

Clelia Dallanoce, Fabio Frigerio, Giovanni Grazioso, Carlo Matera, Giacomo Luca Visconti, Marco De Amici, Luca Pucci, Francesco Pistillo, Sergio Fucile, Cecilia Gotti, Francesco Clementi, Carlo De Micheli

Research output: Contribution to journalArticle

Abstract

A set of structural analogues of spirocyclic quinuclidinyl- Δ2-isoxazolines, characterized as potent and selective α7 nicotinic agonists, was prepared and assayed for binding affinity at α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a-3c, 4a-4c, 5a-5c, 6a-6c, and 7a-7c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the α7 subtype when compared with their model compounds. Solely Δ2-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the α7 nAChRs (Ki = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy α7 vs. α4β2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.

Original languageEnglish
Pages (from-to)5790-5799
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number12
DOIs
Publication statusPublished - Dec 2011

Keywords

  • α7 Selective nicotinic ligands
  • Binding affinity
  • Cycloaddition reaction
  • Electrophysiological assays
  • Molecular modeling
  • Neuronal nicotinic acetylcholine receptors

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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  • Cite this

    Dallanoce, C., Frigerio, F., Grazioso, G., Matera, C., Visconti, G. L., De Amici, M., Pucci, L., Pistillo, F., Fucile, S., Gotti, C., Clementi, F., & De Micheli, C. (2011). New spirocyclic Δ2-isoxazoline derivatives related to selective agonists of α7 neuronal nicotinic acetylcholine receptors. European Journal of Medicinal Chemistry, 46(12), 5790-5799. https://doi.org/10.1016/j.ejmech.2011.09.028