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NEUROPHARMACOLOGY

Pharmacological Characterization of the Competitive GLU_K5 Receptor Antagonist Decahydroisoquinoline LY466195 in Vitro and in Vivo

Eli Lilly and Company, Neuroscience Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (B.W., A.A., A.M.O., M.G., D.K.D., A.C.-S., K.H.H., R.A.W., D.O.C., D.S., E.L.M., R.E.S., B.J., C.S., M.K., L.A.P., K.S., M.C., S.A.F., P.L.O., K.W.J., D.B.); and Allelix Biopharmaceuticals, Mississauga, Ontario, Canada (K.H.H., K.J., G.R.)

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 [(3S,4aR,6S,8aR)-6-[[(2S)-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/-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 GLU_K5 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 GLU_K5, GLU_K2/GLU_K5, or GLU_K5/GLU_K6 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.

Address correspondence to: Dr. David Bleakman, Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285-0510. E-mail: bleakman_david{at}lilly.com

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