Pharmacological Characterization of the Competitive GLUK5 Receptor Antagonist Decahydroisoquinoline LY466195 in Vitro and in Vivo

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU K5 in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in v...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2006-08, Vol.318 (2), p.772-781
Main Authors: Weiss, Brianne, Alt, Andrew, Ogden, Ann Marie, Gates, Mary, Dieckman, Donna K, Clemens-Smith, Amy, Ho, Ken H, Jarvie, Keith, Rizkalla, Geihan, Wright, Rebecca A, Calligaro, David O, Schoepp, Darryle, Mattiuz, Edward L, Stratford, Robert E, Johnson, Bryan, Salhoff, Craig, Katofiasc, Mary, Phebus, Lee A, Schenck, Kathryn, Cohen, Marlene, Filla, Sandra A, Ornstein, Paul L, Johnson, Kirk W, Bleakman, David
Format: Article
Language:English
Subjects:
Animals
Benzodiazepines - pharmacology
Binding, Competitive - drug effects
Blood Proteins - metabolism
Calcium - metabolism
Electrophysiology
Excitatory Amino Acid Antagonists - pharmacology
Humans
In Vitro Techniques
Isoquinolines - pharmacology
Ligands
Male
Migraine Disorders - metabolism
Motor Activity - drug effects
Muscle Contraction - drug effects
Muscle, Smooth, Vascular - drug effects
Neurons - drug effects
Neurons - metabolism
Phencyclidine - pharmacology
Proto-Oncogene Proteins c-fos - biosynthesis
Rabbits
Rats
Receptors, AMPA - antagonists & inhibitors
Receptors, Kainic Acid - antagonists & inhibitors
Saphenous Vein - cytology
Saphenous Vein - drug effects
Transfection
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU K5 in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU K5 -selective kainate receptor antagonist LY466195 [(3 S ,4 aR ,6 S ,8 aR )-6-[[(2 S )-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLU K5 antagonist described to date. Comparisons were made to the competitive GLU K5 /α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3 S ,4 aR ,6 R ,8 aR )-6-[2-(1(2) H -tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU K5 receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5 H -2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 μM)-induced currents with an IC 50 value of 0.045 ± 0.011 μM. In HEK293 cells transfected with GLU K5 , GLU K2 /GLU K5 , or GLU K5 /GLU K6 receptors, LY466195 produced IC 50 values of 0.08 ± 0.02, 0.34 ± 0.17, and 0.07 ± 0.02 μM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID 100 value of 100 μg/kg i.v. LY466195 was also efficacious in the c- fos migraine model, with a dose of 1 μg/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c- fos models after oral administration at doses of 10 and 100 μg/kg, respectively while having no N -methyl- d -aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.106.101428