TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 314 LP - 322 VL - 299 IS - 1 AU - Thierry Canton AU - Georg Andrees Böhme AU - Alain Boireau AU - Françoise Bordier AU - Serge Mignani AU - Patrick Jimonet AU - Ghafoor Jahn AU - Mohammad Alavijeh AU - James Stygall AU - Simon Roberts AU - Clive Brealey AU - Marc Vuilhorgne AU - Marc-William Debono AU - Sylvain Le Guern AU - Michel Laville AU - Dominique Briet AU - Michel Roux AU - Jean-Marie Stutzmann AU - Jeremy Pratt Y1 - 2001/10/01 UR - http://jpet.aspetjournals.org/content/299/1/314.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -