Inhibitors of AMPA and kainate receptors.
The glutamate receptor system is implicated in the development and maintenance of epileptic seizures, and animal studies have disclosed potent anticonvulsant activity of a number of inhibitors of AMPA and/or kainate (KA) receptor activity. These results make such inhibitors potential future antiepileptic drugs. Different series of compounds with inhibitory activity towards AMPA receptors have been developed. Most of these inhibitors are structurally derived from AMPA, quinoxalinedione or 2,3-benzodiazepine. In contrast, only a limited number of inhibitors of KA receptor activity have been developed, most of which contain quinoxalinedione or decahydroisoquinoline skeletons. In spite of promising anticonvulsant activity in various animal model studies, no AMPA/KA receptor inhibitors are in clinical use against epilepsy today. Based on molecular biology studies, AMPA and KA receptors are at present divided into four and five subtypes, respectively, and attempts to develop subtype selective compounds have been initiated. Future studies and development of such compounds will indicate whether AMPA/KA receptor inhibition is a feasible therapeutic strategy for the treatment of epilepsy.
Madsen
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Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, Copenhagen, DK-2100, Denmark. um@dfh.dk
Stensbøl
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Krogsgaard-Larsen
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D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D007608:Kainic Acid / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D000927:Anticonvulsants; D007608:Kainic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid