title: Phosphonate quinoxalinedione AMPA antagonists.
abstract: In the Western world, over 350,000 deaths and $30 billion in medical costs are attributed annually to stroke. Head and spinal cord trauma cause an estimated 250,000 deaths annually and result in medical costs of $15 billion. Although stroke and head/spinal cord trauma are leading causes of disability and death in humans, no adequate neuroprotective treatment is available. Glutamate antagonists derived from the quinoxa-linedione scaffold are as drug candidates for neuroprotection in stroke and trauma. Quinoxalinedione derivatives such as 2,3-dihydroxy-6- nitro-7-sulfamoylbenzo(f)quinoxaline and 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione failed clinical trials because of insolu-bility and resulting nephrotoxicity. Introduction of a phosphonate group into the quinoxalinedione skeleton improves solubility and leaves potency for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor unchanged. Phosphonate quinoxalinedione derivatives ZK202000 and ZK200775 protected rodent brain against sequelae of permanent occlusion of the middle cerebral artery and head trauma. No major deleterious effects on motor coordination, cardiovascular, or respiratory systems were detected in doses required for neuroprotection. No psychotomimetic and no neurotoxic side effects, typical for N-methyl-D-aspartate antagonists, were observed following treatment with phosphonate quinoxalinediones.
authors.affiliation: Research Laboratories of Schering AG, Müllerstrasse 178, D-13342 Berlin, Germany.
authors.forename: Lechoslaw
authors.initials: L
authors.lastname: Turski
authors.forename: Herbert H.
authors.initials: HH
authors.lastname: Schneider
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.forename: Fiona
authors.initials: F
authors.lastname: McDonald
authors.forename: Graham H.
authors.initials: GH
authors.lastname: Jones
authors.forename: Boel
authors.initials: B
authors.lastname: Löfberg
authors.forename: Hermann
authors.initials: H
authors.lastname: Schweinfurth
authors.forename: Andreas
authors.initials: A
authors.lastname: Huth
authors.forename: Martin
authors.initials: M
authors.lastname: Krüger
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ottow