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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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
Issue number2
StatePublished - Jul 21 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Weiss, B., Alt, A., Ogden, A. M., Gates, M., Dieckman, D. K., Clemens-Smith, A., Ho, K. H., Jarvie, K., Rizkalla, G., Wright, R. A., Calligaro, D. O., Schoepp, D., Mattiuz, E. L., Stratford, R. E., Johnson, B., Salhoff, C., Katofiasc, M., Phebus, L. A., Schenck, K., ... Bleakman, D. (2006). Pharmacological characterization of the competitive GLUK5 receptor antagonist decahydroisoquinoline LY466195 in vitro and in vivo. Journal of Pharmacology and Experimental Therapeutics, 318(2), 772-781.