Synthesis of anticonvulsive AMPA antagonists: 4-Oxo-10-substituted-imidazo[1,2- a]indeno[1,2- e]pyrazin-2-carboxylic acid derivatives
The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series of readily water soluble 4-oxo-10-substituted-imidazo[1,2- a]indeno[1,2...
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Published in | Bioorganic & medicinal chemistry letters Vol. 11; no. 9; pp. 1205 - 1210 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Oxford
Elsevier Ltd
07.05.2001
Elsevier |
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Abstract | The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series of readily water soluble 4-oxo-10-substituted-imidazo[1,2-
a]indeno[1,2-
e]pyrazin-2-carboxylic acid derivatives was synthesized. The most potent derivative
6a exhibited nanomolar binding affinity (IC
50=35
nM) and antagonist activity (IC
50=6
nM) at ionotropic AMPA receptor. This compound also demonstrated potent anticonvulsant properties in MES in mice and rats with long durations of action with ED
50 values in the 1–3
mg/kg dose range following ip and iv administration.
The 4-oxo-imidazo[1,2-
a]indeno[1,2-
e]pyrazin-2-carboxylic acid
1 exhibited strong binding affinity for the AMPA receptor (IC
50=35
nM) and potent antagonist activity against electrophysiological responses (IC
50=6
nM). Compound
1 demonstrated also an anticonvulsant effect at low doses in MES test with ED
50 values between 1 and 3 mg/kg dose range following ip and iv administration (mouse) and extended long duration of action following iv administration (mouse and rats). |
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AbstractList | The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series of readily water soluble 4-oxo-10-substituted-imidazo[1,2-
a]indeno[1,2-
e]pyrazin-2-carboxylic acid derivatives was synthesized. The most potent derivative
6a exhibited nanomolar binding affinity (IC
50=35
nM) and antagonist activity (IC
50=6
nM) at ionotropic AMPA receptor. This compound also demonstrated potent anticonvulsant properties in MES in mice and rats with long durations of action with ED
50 values in the 1–3
mg/kg dose range following ip and iv administration.
The 4-oxo-imidazo[1,2-
a]indeno[1,2-
e]pyrazin-2-carboxylic acid
1 exhibited strong binding affinity for the AMPA receptor (IC
50=35
nM) and potent antagonist activity against electrophysiological responses (IC
50=6
nM). Compound
1 demonstrated also an anticonvulsant effect at low doses in MES test with ED
50 values between 1 and 3 mg/kg dose range following ip and iv administration (mouse) and extended long duration of action following iv administration (mouse and rats). |
Author | Ribeill, Yves Bohme, Georg Andrees Debono, Marc Williams Boireau, Alain Genevois-Borella, Arielle Jimonet, Patrick Randle, John C.R Vuilhorgne, Marc Mignani, Serge Damour, Dominique Stutzmann, Jean-Marie Pratt, Jeremy |
Author_xml | – sequence: 1 givenname: Jean-Marie surname: Stutzmann fullname: Stutzmann, Jean-Marie – sequence: 2 givenname: Georg Andrees surname: Bohme fullname: Bohme, Georg Andrees – sequence: 3 givenname: Alain surname: Boireau fullname: Boireau, Alain – sequence: 4 givenname: Dominique surname: Damour fullname: Damour, Dominique – sequence: 5 givenname: Marc Williams surname: Debono fullname: Debono, Marc Williams – sequence: 6 givenname: Arielle surname: Genevois-Borella fullname: Genevois-Borella, Arielle – sequence: 7 givenname: Patrick surname: Jimonet fullname: Jimonet, Patrick – sequence: 8 givenname: Jeremy surname: Pratt fullname: Pratt, Jeremy – sequence: 9 givenname: John C.R surname: Randle fullname: Randle, John C.R – sequence: 10 givenname: Yves surname: Ribeill fullname: Ribeill, Yves – sequence: 11 givenname: Marc surname: Vuilhorgne fullname: Vuilhorgne, Marc – sequence: 12 givenname: Serge surname: Mignani fullname: Mignani, Serge email: serge.mignani@aventis.com |
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Keywords | Intraperitoneal administration Intravenous administration Rat Angular nitrogen heterocycle Central nervous system Lactam Anticonvulsant Glutamate receptor Structure activity relation Aromatic compound Antagonist Chemical synthesis Neurological disorder Rodentia Tetracyclic compound In vitro Vertebrata Chemotherapy Experimental disease AMPA receptor Mammalia Treatment Convulsion Mouse Animal Affinity Brain (vertebrata) |
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Snippet | The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as... |
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StartPage | 1205 |
SubjectTerms | Anticonvulsants. Antiepileptics. Antiparkinson agents Biological and medical sciences Medical sciences Neuropharmacology Pharmacology. Drug treatments |
Title | Synthesis of anticonvulsive AMPA antagonists: 4-Oxo-10-substituted-imidazo[1,2- a]indeno[1,2- e]pyrazin-2-carboxylic acid derivatives |
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