AMPA receptor antagonists with additional mechanisms of action: new opportunities for neuroprotective drugs?
Ischaemic stroke of the brain accounts for about one third of all deaths in industrialized countries. Many of the patients who survive are severily impaired. Thus, there is an enormous need for pharmacotherapy for the treatment of ischaemic stroke. Why is such a treatment not available yet? Are the pathophysiological sequelae of brain ischaemia not well understood? Have there been no attempts for clinical development of neuroprotective drugs? Everyone who is engaged in stroke research knows that the opposite is true: The cellular processes occuring after brain ischaemia have been studied for a long time, and we have a thorough understanding of the cellular processes which are involved. Many compounds underwent clinical trials, but most of them failed. One hypothesis to explain this disappointing fact might be that the cellular consequences of stroke are manyfold, but that the clinically tested compounds were selective for only one molecular mechanism. The aim of this review is to give a summary of the pathophysiological mechanisms which occur during and after an ischaemic stroke, and to comment on the preclinical studies where multiple disease-related mechanisms were targeted pharmacologically. Moreover, a novel class of neuroprotective compounds, the oxadiazole derivatives, will be presented. Compounds of this chemical class target two key mechanisms which are important for the pathophysiology of stroke, namely voltage-gated sodium channels, as well as glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype.
Weiser
Thomas
T
Department CNS Research, Boehringer Ingelheim Pharma KG, Binger Strasse, Ingelheim, D-55216, Germany. weiser@ing.boehringer-ingelheim.com
D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
C464487:BIIR 561; D018691:Excitatory Amino Acid Antagonists; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D010069:Oxadiazoles; D018091:Receptors, AMPA