Ethyl (3S,4aR,6S,8aR)-6-(4-Ethoxycar- bonylimidazol-1-ylmethyl)decahydroiso- quinoline-3-carboxylic Ester:  A Prodrug of a GluR5 Kainate Receptor Antagonist Active in Two Animal Models of Acute Migraine

Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine:  the neurogenic dural plasma protein extravasation model a...

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Published in:Journal of medicinal chemistry 2002-09, Vol.45 (20), p.4383-4386
Main Authors: Filla, Sandra A, Winter, Mark A, Johnson, Kirk W, Bleakman, David, Bell, Michael G, Bleisch, Thomas J, Castaño, Ana M, Clemens-Smith, Amy, del Prado, Miriam, Dieckman, Donna K, Dominguez, Esteban, Escribano, Ana, Ho, Ken H, Hudziak, Kevin J, Katofiasc, Mary A, Martinez-Perez, Jose A, Mateo, Ana, Mathes, Brian M, Mattiuz, Edward L, Ogden, Ann Marie L, Phebus, Lee A, Stack, Douglas R, Stratford, Robert E, Ornstein, Paul L
Format: Article
Language:English
Subjects:
Acute Disease
Administration, Oral
Animals
Biological Availability
Calcium - metabolism
Carboxylic Acids - chemical synthesis
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Cell Line
Disease Models, Animal
Dose-Response Relationship, Drug
Esters - chemical synthesis
Esters - chemistry
Esters - pharmacology
Excitatory Amino Acid Antagonists - chemical synthesis
Excitatory Amino Acid Antagonists - chemistry
Excitatory Amino Acid Antagonists - pharmacology
Humans
Isoquinolines - chemical synthesis
Isoquinolines - chemistry
Isoquinolines - pharmacology
Migraine Disorders - drug therapy
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
Radioligand Assay
Rats
Rats, Wistar
Receptors, Kainic Acid - antagonists & inhibitors
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Summary:Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine:  the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm025548q