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Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and evaluation as NMDA receptor antagonists

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Abstract

N-Methyl-d-aspartate (NMDA) receptor antagonists are known to rescue neuronal cell death caused by excessive activation of glutamate receptors. This phenomenon, known as excitotoxicity, is implicated in the pathogenesis of several neurodegenerative disorders including ischemia, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Unfortunately, some NMDA receptor antagonists have shown discouraging results when tested in clinical trials. However, recent advances in the physiology and pharmacology of the NMDA receptor have kept interest alive in modulating NMDA receptors for therapeutic intervention. We present here the synthesis of a small library of phenylalaninol-derived oxazolopyrrolidone lactams and their evaluation as NMDA receptor antagonists. The compounds were easily synthesized in yields up to 92 %. In addition, one of the compounds has a 50 % inhibitory concentration (IC 50) of 62 μM and offers potential to develop more potent NMDA receptor antagonists.

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Acknowledgments

Fundação para a Ciência e Tecnologia (Portugal) is acknowledged for financial support (PTDC/QUI-QUI/111664/2009; PEst-OE/SAU/UI4013/2011; REDE/1518/REM/2005). We also thank the Portuguese–Spanish Integrated Action (E-07/11 and AIB2010PT-00324) and the Spanish Ministerio de Ciencia e Innovación (MICINN) (CTQ2009-07021/BQU) for financial support.

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Authors and Affiliations

  1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Nuno A. L. Pereira & Maria M. M. Santos

  2. Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, c./St. Llorenç 21, 43201, Reus, Tarragona, Spain

    Francesc X. Sureda & Mireia Turch

  3. Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, s/n, 08028, Barcelona, Spain

    Mercedes Amat & Joan Bosch

Authors
  1. Nuno A. L. Pereira
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  2. Francesc X. Sureda
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  3. Mireia Turch
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  4. Mercedes Amat
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  5. Joan Bosch
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  6. Maria M. M. Santos
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Corresponding author

Correspondence to Maria M. M. Santos.

Additional information

Dedicated to Professor Sundaresan Prabhakar on the occasion of his 75th anniversary.

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Pereira, N.A.L., Sureda, F.X., Turch, M. et al. Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and evaluation as NMDA receptor antagonists. Monatsh Chem 144, 473–477 (2013). https://doi.org/10.1007/s00706-012-0880-8

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  • DOI: https://doi.org/10.1007/s00706-012-0880-8

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