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Research ArticleNEUROPHARMACOLOGY

RPR 119990, a Novel α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Antagonist: Synthesis, Pharmacological Properties, and Activity in an Animal Model of Amyotrophic Lateral Sclerosis

Thierry Canton, Georg Andrees Böhme, Alain Boireau, Françoise Bordier, Serge Mignani, Patrick Jimonet, Ghafoor Jahn, Mohammad Alavijeh, James Stygall, Simon Roberts, Clive Brealey, Marc Vuilhorgne, Marc-William Debono, Sylvain Le Guern, Michel Laville, Dominique Briet, Michel Roux, Jean-Marie Stutzmann and Jeremy Pratt
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 314-322;
Thierry Canton
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Georg Andrees Böhme
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Alain Boireau
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Françoise Bordier
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Serge Mignani
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Patrick Jimonet
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Ghafoor Jahn
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Mohammad Alavijeh
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James Stygall
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Simon Roberts
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Clive Brealey
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Marc Vuilhorgne
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Marc-William Debono
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Sylvain Le Guern
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Michel Laville
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Michel Roux
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Jean-Marie Stutzmann
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Jeremy Pratt
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Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid (RPR 119990). The compound displaced [3H]AMPA from rat cortex membranes with a Ki of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a KB of 71 nM. The antagonist properties of this compound were confirmed on rat native AMPA receptors in cerebella granule neurons in culture and in hippocampal slices where it antagonized electrophysiological responses with IC50 values of 50 and 93 nM, respectively. RPR 119990 antagonized hippocampal evoked responses in vivo, demonstrating brain penetration at active concentrations. RPR 119990 is a potent anticonvulsant in the supramaximal electroshock in the mouse with an ED50 of 2.3 mg/kg 1 h post s.c. administration, giving it a workably long action. Pharmacokinetic studies show good passage into the plasma after subcutaneous administration, whereas brain penetration is low but with slow elimination. This compound was found active in a transgenic mouse model of familial amyotrophic lateral sclerosis (SOD1-G93A) where it was able to improve grip muscle strength and glutamate uptake from spinal synaptosomal preparations, and prolong survival with a daily dose of 3 mg/kg s.c.

Footnotes

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    ALS
    amyotrophic lateral sclerosis
    SOD1
    Cu, Zn superoxide dismutase
    PK
    pharmacokinetics
    ACSF
    artificial cerebrospinal fluid
    EPSP
    excitatory postsynaptic potential
    Cpmax
    maximum plasma concentration
    AUC
    area under the curve
    • Received May 7, 2001.
    • Accepted June 26, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleNEUROPHARMACOLOGY

RPR 119990, a Novel α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Antagonist: Synthesis, Pharmacological Properties, and Activity in an Animal Model of Amyotrophic Lateral Sclerosis

Thierry Canton, Georg Andrees Böhme, Alain Boireau, Françoise Bordier, Serge Mignani, Patrick Jimonet, Ghafoor Jahn, Mohammad Alavijeh, James Stygall, Simon Roberts, Clive Brealey, Marc Vuilhorgne, Marc-William Debono, Sylvain Le Guern, Michel Laville, Dominique Briet, Michel Roux, Jean-Marie Stutzmann and Jeremy Pratt
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 314-322;

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Research ArticleNEUROPHARMACOLOGY

RPR 119990, a Novel α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Antagonist: Synthesis, Pharmacological Properties, and Activity in an Animal Model of Amyotrophic Lateral Sclerosis

Thierry Canton, Georg Andrees Böhme, Alain Boireau, Françoise Bordier, Serge Mignani, Patrick Jimonet, Ghafoor Jahn, Mohammad Alavijeh, James Stygall, Simon Roberts, Clive Brealey, Marc Vuilhorgne, Marc-William Debono, Sylvain Le Guern, Michel Laville, Dominique Briet, Michel Roux, Jean-Marie Stutzmann and Jeremy Pratt
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 314-322;
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