title: 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.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA. filla_sandra_a@lilly.com
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Filla
authors.forename: Mark A
authors.initials: MA
authors.lastname: Winter
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
authors.forename: Michael G
authors.initials: MG
authors.lastname: Bell
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bleisch
authors.forename: Ana M
authors.initials: AM
authors.lastname: Castaño
authors.forename: Amy
authors.initials: A
authors.lastname: Clemens-Smith
authors.forename: Miriam
authors.initials: M
authors.lastname: del Prado
authors.forename: Donna K
authors.initials: DK
authors.lastname: Dieckman
authors.forename: Esteban
authors.initials: E
authors.lastname: Dominguez
authors.forename: Ana
authors.initials: A
authors.lastname: Escribano
authors.forename: Ken H
authors.initials: KH
authors.lastname: Ho
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hudziak
authors.forename: Mary A
authors.initials: MA
authors.lastname: Katofiasc
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Perez
authors.forename: Ana
authors.initials: A
authors.lastname: Mateo
authors.forename: Brian M
authors.initials: BM
authors.lastname: Mathes
authors.forename: Edward L
authors.initials: EL
authors.lastname: Mattiuz
authors.forename: Ann Marie L
authors.initials: AM
authors.lastname: Ogden
authors.forename: Lee A
authors.initials: LA
authors.lastname: Phebus
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stack
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stratford
authors.forename: Paul L
authors.initials: PL
authors.lastname: Ornstein
mesh_terms: 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*
chemical_list: 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