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.

01 Nov 1998·Brain Research BulletinQ3 · MEDICINE

Effects of N-methyl-d-aspartate antagonists on different measures of motion sickness in cats

Q3 · MEDICINE

Article

Author: Lucot, J B

Because N-methyl-D-aspartate (NMDA) antagonists prevent cisplatin-induced emesis and NMDA receptors are in both emetic pathways and structures associated with the final common pathway for vomiting, they have the potential to be broad-spectrum antiemetics. This was evaluated by determining their effects on motion sickness in cats. The measures included the number vomiting, the number of symptom points, which reflect activity early in the final common path and the duration of the retch/vomit sequence, which reflects activity late in the path. Dextrorphan, ketamine and dextromethorphan decreased the number vomiting with the same rank order of potency as at NMDA receptors. Additional studies with 1,3-dio-tolylguaninidine (DTG) and haloperidol ruled out a role for sigma receptors. The NMDA antagonists produced a nonsignificant dose-dependent decrease in symptoms and had no effects on the duration of vomiting. They also produced motor abnormalities at the highest doses. The competitive antagonist LY 233053 also decreased the number vomiting without altering the duration. It produced a nonsignificant non-dose-dependent decrease in symptoms and had no effects on gross motor output. The results are consistent with a broad spectrum of antiemetic efficacy with at least a part of its action in the early to middle portions of the final common pathway for vomiting. Additional actions on the vestibular nuclei are possible.

01 Feb 1998·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Heteroatom-substitution as a strategy for increasing the potency of competitive NMDA antagonists

Q4 · MEDICINE

Article

Author: William H.W. Lunn ; David Lodge ; Lawrence J. Heinz ; Darryle D. Schoepp ; M.Brian Arnold ; Paul L. Ornstein ; J.David Leander

We report the synthesis and characterization of compounds that are competitive NMDA receptor antagonists. Significant increases in affinity and potency were obtained by incorporation of a heteroatom into the substructure of the tetrazole-substituted amino acid LY233053.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Ischemia	Discovery	US	Eli Lilly & Co.	01 Dec 1990
Seizures	Discovery	US	Eli Lilly & Co.	01 Dec 1990

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