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 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.
Filla
Sandra A
SA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA. filla_sandra_a@lilly.com
Winter
Mark A
MA
Johnson
Kirk W
KW
Bleakman
David
D
Bell
Michael G
MG
Bleisch
Thomas J
TJ
Castaño
Ana M
AM
Clemens-Smith
Amy
A
del Prado
Miriam
M
Dieckman
Donna K
DK
Dominguez
Esteban
E
Escribano
Ana
A
Ho
Ken H
KH
Hudziak
Kevin J
KJ
Katofiasc
Mary A
MA
Martinez-Perez
Jose A
JA
Mateo
Ana
A
Mathes
Brian M
BM
Mattiuz
Edward L
EL
Ogden
Ann Marie L
AM
Phebus
Lee A
LA
Stack
Douglas R
DR
Stratford
Robert E
RE
Ornstein
Paul L
PL
D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008881:Migraine Disorders / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*
D002118:Calcium; D002264:Carboxylic Acids; D004952:Esters; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D011355:Prodrugs; D018092:Kainic Acid Receptors; C466804:6-(4-carboxyimidazol-1-ylmethyl)decahydroisoquinoline-3-carboxylic acid; C466633:ethyl 6-(4-ethoxycarbonylimidazol-1-ylmethyl)decahydroisoquinoline-3-carboxylic ester