title: RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis.
abstract: Alpha-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 K(i) of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a K(B) 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.
authors.affiliation: Aventis Pharma S.A., Neurodegenerative Disease Group, Vitry-Sur-Seine Cedex, France.
authors.forename: T
authors.initials: T
authors.lastname: Canton
authors.forename: G A
authors.initials: GA
authors.lastname: Böhme
authors.forename: A
authors.initials: A
authors.lastname: Boireau
authors.forename: F
authors.initials: F
authors.lastname: Bordier
authors.forename: S
authors.initials: S
authors.lastname: Mignani
authors.forename: P
authors.initials: P
authors.lastname: Jimonet
authors.forename: G
authors.initials: G
authors.lastname: Jahn
authors.forename: M
authors.initials: M
authors.lastname: Alavijeh
authors.forename: J
authors.initials: J
authors.lastname: Stygall
authors.forename: S
authors.initials: S
authors.lastname: Roberts
authors.forename: C
authors.initials: C
authors.lastname: Brealey
authors.forename: M
authors.initials: M
authors.lastname: Vuilhorgne
authors.forename: M W
authors.initials: MW
authors.lastname: Debono
authors.forename: S
authors.initials: S
authors.lastname: Le Guern
authors.forename: M
authors.initials: M
authors.lastname: Laville
authors.forename: D
authors.initials: D
authors.lastname: Briet
authors.forename: M
authors.initials: M
authors.lastname: Roux
authors.forename: J M
authors.initials: JM
authors.lastname: Stutzmann
authors.forename: J
authors.initials: J
authors.lastname: Pratt
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D018450:Disease Progression; D004594:Electrophysiology; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D018698:Glutamic Acid / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011719:Pyrazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: C436739:9-carboxymethyl-4-oxo-5H,10H-imidazo(1,2-a)indeno(1,2-e)pyrazin-2-phosphonic acid; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D011719:Pyrazines; D018091:Receptors, AMPA; D018698:Glutamic Acid; D013482:Superoxide Dismutase