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.
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.
Mignani
Serge
S
Aventis Pharma S.A., Centre de Recherche de Paris, Vitry-sur-Seine Cedex, France. serge.mignani@aventis.com
Bohme
Georg Andrees
GA
Birraux
Guillaume
G
Boireau
Alain
A
Jimonet
Patrick
P
Damour
Dominique
D
Genevois-Borella
Arielle
A
Debono
Marc Williams
MW
Pratt
Jeremy
J
Vuilhorgne
Marc
M
Wahl
Florence
F
Stutzmann
Jean Marie
JM
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001930:Brain Injuries / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy; D004195:Disease Models, Animal; D005849:Gerbillinae; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000188:drug therapy; D012640:Seizures / Q000188:drug therapy; D013117:Spinal Cord Compression / Q000188:drug therapy; D013569:Synapses / Q000187:drug effects; D014981:Xenopus
D000927:Anticonvulsants; D007093:Imidazoles; D018696:Neuroprotective Agents; D011719:Pyrazines; C473371:RPR 117824; D018091:Receptors, AMPA