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Research ArticleDrug Discovery and Translational Medicine

ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7 (mGlu7): in vitro and in vivo characterization

Mikhail Kalinichev, Melanie Rouillier, Francoise Girard, Isabelle Royer-Urios, Bruno Bournique, Terry Finn, Delphine Charvin, Brice Campo, Emmanuel Le Poul, Vincent Mutel, Sonia Poli, Stuart A neale, Thomas E Salt and Robert Lutjens
Journal of Pharmacology and Experimental Therapeutics December 20, 2012, jpet.112.200915; DOI: https://doi.org/10.1124/jpet.112.200915
Mikhail Kalinichev
1 Addex Therapeutics;
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Melanie Rouillier
1 Addex Therapeutics;
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Francoise Girard
1 Addex Therapeutics;
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Isabelle Royer-Urios
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Bruno Bournique
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Terry Finn
1 Addex Therapeutics;
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Delphine Charvin
1 Addex Therapeutics;
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Brice Campo
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Emmanuel Le Poul
1 Addex Therapeutics;
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Vincent Mutel
1 Addex Therapeutics;
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Sonia Poli
1 Addex Therapeutics;
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Stuart A neale
2 Neurexpert;
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Thomas E Salt
3 UCL Institute of Ophtamology
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Robert Lutjens
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Abstract

Metabotropic glutamate receptor 7 (mGlu7) has been suggested to be a promising novel target for treatment of a range of disorders including anxiety, PTSD, depression, drug abuse and schizophrenia. In this study we characterized a potent and selective mGlu7 negative allosteric modulator (NAM) ADX71743. In vitro, Schild plot analysis and reversibility test at the target confirmed the NAM properties of the compound and attenuation of L-AP4-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice revealed that it is bioavailable following subcutaneous administration and brain-penetrant (CSF concentration/total plasma concentration ratio = 0.8%). In vivo, ADX71743 (50, 100, 150 mg/kg s.c.) caused no impairment of locomotor activity in rats and mice and activity on rotarod in mice. ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open-arm exploration, respectively. While ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse DOI-induced head twitch and the rat conditioned avoidance response tests. Also, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiological role of mGlu7 and understand better its implication in CNS diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu7 is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.

  • allosterism
  • anxiety
  • drug discovery
  • metabotropic receptors
  • Received October 3, 2012.
  • Revision received December 16, 2012.
  • Accepted December 18, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7 (mGlu7): in vitro and in vivo characterization

Mikhail Kalinichev, Melanie Rouillier, Francoise Girard, Isabelle Royer-Urios, Bruno Bournique, Terry Finn, Delphine Charvin, Brice Campo, Emmanuel Le Poul, Vincent Mutel, Sonia Poli, Stuart A neale, Thomas E Salt and Robert Lutjens
Journal of Pharmacology and Experimental Therapeutics December 20, 2012, jpet.112.200915; DOI: https://doi.org/10.1124/jpet.112.200915

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Research ArticleDrug Discovery and Translational Medicine

ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7 (mGlu7): in vitro and in vivo characterization

Mikhail Kalinichev, Melanie Rouillier, Francoise Girard, Isabelle Royer-Urios, Bruno Bournique, Terry Finn, Delphine Charvin, Brice Campo, Emmanuel Le Poul, Vincent Mutel, Sonia Poli, Stuart A neale, Thomas E Salt and Robert Lutjens
Journal of Pharmacology and Experimental Therapeutics December 20, 2012, jpet.112.200915; DOI: https://doi.org/10.1124/jpet.112.200915
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