9-Carboxymethyl-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-2-carbocylic acid (RPR117824): Selective anticonvulsive and neuroprotective AMPA antagonist

• Published in: Bioorganic & medicinal chemistry Vol. 10; no. 5; pp. 1627 - 1637
• Main Authors: MIGNANI, Serge, BOHME, Georg Andrees, WAHL, Florence, STUTZMANN, Jean-Marie, BIRRAUX, Guillaume, BOIREAU, T. Alain, JIMONET, Patrick, DAMOUR, Dominique, GENEVOIS-BORELLA, Arielle, DEBONO, Marc-Williams, PRATT, Jeremy, VUILHORGNE, Marc
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.05.2002
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Brain Injuries - drug therapy; Brain Ischemia - drug therapy; Disease Models, Animal; Gerbillinae; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Male; Medical sciences; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oocytes; Pharmacology. Drug treatments; Protein Binding; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - pharmacology; Radioligand Assay; Rats; Receptors, AMPA - antagonists & inhibitors; Reperfusion Injury - drug therapy; Seizures - drug therapy; Spinal Cord Compression - drug therapy; Synapses - drug effects; Xenopus; Rat; Angular nitrogen heterocycle; Rodentia; Anticonvulsant; Neuroprotective agent; Glutamate receptor; Tetracyclic compound; In vitro; Trauma; In vivo; Vertebrata; Experimental disease; Mammalia; Ischemia; Structure activity relation; Mouse; Carboxylic acid; Animal; Aromatic compound; Antagonist; NMDA receptor; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00431-X

Excessive release of glutamate, a potent excitatory neurotransmitter, is thought to play an important role in a variety of acute and chronic neurological disorders, suggesting that excitatory amino acid antagonists may have broad therapeutic potential in neurology. Here, we describe the synthesis, pharmacological properties and neuroprotective activity of 9-carboxymethyl-imidazo-[1-2a]indeno[1-2e]pyrazin-4-one-2-carboxylic acid (RPR117824), an original selective AMPA antagonist. RPR117824 can be obtained through a six-step synthesis starting from (1-oxo-indan-4-yl) acetic acid, which has been validated on a gram-scale with an overall yield of 25%. Monosodium or disodium salts of the compound exhibit excellent solubility in saline (> or = 10 g/L), enabling intravenous administration. RPR117824 displays nanomolar affinity (IC(50)=18 nM) for AMPA receptors and competitive inhibition of electrophysiological responses mediated by AMPA receptors heterologously expressed in Xenopus oocytes (K(B)=5 nM) and native receptors in rat brain slices (IC(50)=0.36 microM). In in vivo testing, RPR117824 behaves as a powerful blocker of convulsions induced in mice or rats by supramaximal electroshock or chemoconvulsive agents such as pentylenetetrazole, bicuculline, isoniazide, strychnine, 4-aminopyridine and harmaline with half maximal effective doses ranging from 1.5 to 10 mg/kg following subcutaneous or intraperitoneal administration. In disease models in rats and gerbils, RPR117824 possesses significant neuroprotective activity in global and focal cerebral ischemia, and brain and spinal cord trauma.