Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo

Brianne Weiss, Andrew Alt, Ann Marie Ogden, Mary Gates, Donna K. Dieckman, Amy Clemens-Smith, Ken H. Ho, Keith Jarvie, Geihan Rizkalla, Rebecca A. Wright, David O. Calligaro, Darryle Schoepp, Edward L. Mattiuz, Robert E. Stratford, Bryan Johnson, Craig Salhoff, Mary Katofiasc, Lee A. Phebus, Kathryn Schenck, Marlene CohenSandra A. Filla, Paul L. Ornstein, Kirk W. Johnson, David Bleakman

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Abstract

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLUK5 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 GLUK5-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1- pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLUK5 antagonist described to date. Comparisons were made to the competitive GLUK5/α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H- tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLUK5 receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 μM)-induced currents with an IC50 value of 0.045 ± 0.011 μM. In HEK293 cells transfected with GLUK5, GLUK2/GLUK5, or GLUK5/GLUK6 receptors, LY466195 produced IC50 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 ID100 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.

Original languageEnglish (US)
Pages (from-to)772-781
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume318
Issue number2
DOIs
StatePublished - Jul 21 2006

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6-((2-carboxy-4,4-difluoro-1-pyrrolidinyl)methyl)decahydro-3-isoquinolinecarboxylic acid
Pharmacology
Migraine Disorders
Kainic Acid Receptors
Trigeminal Ganglion
AMPA Receptors
Spinal Ganglia
GYKI 53655
tezampanel
Inhibitory Concentration 50
Blood Proteins
Azepines
Isoxazoles
Gluk1 kainate receptor
In Vitro Techniques
HEK293 Cells
Kainic Acid
Saphenous Vein
Prodrugs
N-Methylaspartate

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo. / 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.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 318, No. 2, 21.07.2006, p. 772-781.

Research output: Contribution to journalArticle

Weiss, B, Alt, A, Ogden, AM, Gates, M, Dieckman, DK, Clemens-Smith, A, Ho, KH, Jarvie, K, Rizkalla, G, Wright, RA, Calligaro, DO, Schoepp, D, Mattiuz, EL, Stratford, RE, Johnson, B, Salhoff, C, Katofiasc, M, Phebus, LA, Schenck, K, Cohen, M, Filla, SA, Ornstein, PL, Johnson, KW & Bleakman, D 2006, 'Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo', Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 2, pp. 772-781. https://doi.org/10.1124/jpet.106.101428
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. / Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 318, No. 2. pp. 772-781.
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title = "Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo",
abstract = "The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLUK5 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 GLUK5-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1- pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLUK5 antagonist described to date. Comparisons were made to the competitive GLUK5/α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H- tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLUK5 receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 μM)-induced currents with an IC50 value of 0.045 ± 0.011 μM. In HEK293 cells transfected with GLUK5, GLUK2/GLUK5, or GLUK5/GLUK6 receptors, LY466195 produced IC50 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 ID100 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.",
author = "Brianne Weiss and Andrew Alt and Ogden, {Ann Marie} and Mary Gates and Dieckman, {Donna K.} and Amy Clemens-Smith and Ho, {Ken H.} and Keith Jarvie and Geihan Rizkalla and Wright, {Rebecca A.} and Calligaro, {David O.} and Darryle Schoepp and Mattiuz, {Edward L.} and Stratford, {Robert E.} and Bryan Johnson and Craig Salhoff and Mary Katofiasc and Phebus, {Lee A.} and Kathryn Schenck and Marlene Cohen and Filla, {Sandra A.} and Ornstein, {Paul L.} and Johnson, {Kirk W.} and David Bleakman",
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T1 - Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo

AU - Weiss, Brianne

AU - Alt, Andrew

AU - Ogden, Ann Marie

AU - Gates, Mary

AU - Dieckman, Donna K.

AU - Clemens-Smith, Amy

AU - Ho, Ken H.

AU - Jarvie, Keith

AU - Rizkalla, Geihan

AU - Wright, Rebecca A.

AU - Calligaro, David O.

AU - Schoepp, Darryle

AU - Mattiuz, Edward L.

AU - Stratford, Robert E.

AU - Johnson, Bryan

AU - Salhoff, Craig

AU - Katofiasc, Mary

AU - Phebus, Lee A.

AU - Schenck, Kathryn

AU - Cohen, Marlene

AU - Filla, Sandra A.

AU - Ornstein, Paul L.

AU - Johnson, Kirk W.

AU - Bleakman, David

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N2 - The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLUK5 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 GLUK5-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1- pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLUK5 antagonist described to date. Comparisons were made to the competitive GLUK5/α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H- tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLUK5 receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 μM)-induced currents with an IC50 value of 0.045 ± 0.011 μM. In HEK293 cells transfected with GLUK5, GLUK2/GLUK5, or GLUK5/GLUK6 receptors, LY466195 produced IC50 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 ID100 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.

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