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

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 latera l 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-phos phonic acid (RPR 119990). The compound displaced [H-3]AMPA from rat cortex membranes with a K-i of 107 nM. In oocytes expressing human recombinant AMP A receptors, RPR 119990 depressed ion flux with a K-B of 71 nM. The antagon ist 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 n M, respectively. RPR 119990 antagonized hippocampal evoked responses in viv o, 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 lon g action. Pharmacokinetic studies show good passage into the plasma after s ubcutaneous 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 imp rove grip muscle strength and glutamate uptake from spinal synaptosomal pre parations, and prolong survival with a daily dose of 3 mg/kg s.c.