Design, Synthesis, and Pharmacological Characterization of Novel Spirocyclic Quinuclidinyl-Δ2-Isoxazoline Derivatives as Potent and Selective Agonists of α7 Nicotinic Acetylcholine Receptors

Authors

  • Dr. Clelia Dallanoce,

    1. Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
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  • Dr. Pietro Magrone,

    1. Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
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  • Dr. Carlo Matera,

    1. Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
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  • Dr. Fabio Frigerio,

    1. Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
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  • Dr. Giovanni Grazioso,

    1. Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
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  • Prof. Marco De Amici,

    1. Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
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  • Prof. Sergio Fucile,

    1. Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza, Piazzale A. Moro 5, 00185 Rome (Italy)
    2. Istituto Neurologico Mediterraneo Neuromed, Via Atinese 18, 86077 Pozzilli (Italy)
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  • Dr. Vanessa Piccari,

    1. Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza, Piazzale A. Moro 5, 00185 Rome (Italy)
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  • Prof. Karla Frydenvang,

    1. Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Dr. Luca Pucci,

    1. CNR, Istituto di Neuroscienze, Farmacologia Cellulare e Molecolare, Dipartimento Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milan (Italy)
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  • Dr. Cecilia Gotti,

    1. CNR, Istituto di Neuroscienze, Farmacologia Cellulare e Molecolare, Dipartimento Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milan (Italy)
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  • Prof. Francesco Clementi,

    1. CNR, Istituto di Neuroscienze, Farmacologia Cellulare e Molecolare, Dipartimento Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milan (Italy)
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  • Prof. Carlo De Micheli

    Corresponding author
    1. Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
    • Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan (Italy), Fax: (+39) 02-50319326
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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 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 α7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 nM, 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 Ki values of 4.6 and 48.7 nM against rat and human α7 receptors, respectively.

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