The NMDA receptor complex: a promising target for novel antiepileptic strategies.
Antiepileptic drugs (AEDs) cover a broad spectrum of pathological conditions ranging from seizures following congenital or acquired brain disorders to behavioural and psychiatric disorders and recently neuropathic pain. The need for novel antiepileptics raises from the expanding field of indications as well as from the fact, that special seizure types are refractory to common AEDs. In addition, many of the conventional antiepileptic drugs exhibit an unfavourable side-effect profile. Since there is growing evidence, that NMDA receptor activation might play a crucial role in epilepsy, NMDA receptor antagonists have become compounds of interest in preventing and treating seizures. This review focuses on NMDA receptor antagonistic compounds, which are already in use for the treatment of epileptic seizures (i. e. MgSO4, felbamate) and compounds in clinical trials (i. e. remacemide, ADCI). Further interest is put on NMDA antagonists in preclinical and biological testing (memantine, dizocilpine, conantokins, Co101244/PD174494, ifenprodil, arcaine, L-701,324, eliprodil, CGP40116, LY235959, LY233053, MRZ2/576, LU73068, 4-Cl-KYN). Some of the latter compounds are predominantely of academic interest (i. e. 4-Cl-KYN), others (i. e. dizocilpine, LY235959, LY233053) might be of therapeutical value when combined with conventional AEDs. In order to reduce adverse effects in antiepileptic medication using NMDA antagonists, special interest will be focused on subtype selective compounds. In this respect, Co101244, a novel potent and selective NR1/2B NMDA receptor antagonist might be a lead for therapeutically promising compounds.
Kohl
B K
BK
Institute of Pharmacy, Johannes Gutenberg-University, Staudinger Weg 5, Mainz, D-55099, Germany. kohl@mail.uni-mainz.de
Dannhardt
G
G
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D016202:N-Methylaspartate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate