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)/alpha-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 microM)-induced currents with an IC50 value of 0.045 +/- 0.011 microM. 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 microM, respectively.
LY466195 was efficacious in a dural
plasma protein extravasation (PPE) model of
migraine with an ID100 value of 100 microg/kg i.v.
LY466195 was also efficacious in the c-fos
migraine model, with a dose of 1 microg/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 microg/kg, respectively while having no
N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.