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 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.
authors.affiliation: Eli Lilly and Company, Neuroscience Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
authors.forename: Brianne
authors.initials: B
authors.lastname: Weiss
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Ogden
authors.forename: Mary
authors.initials: M
authors.lastname: Gates
authors.forename: Donna K
authors.initials: DK
authors.lastname: Dieckman
authors.forename: Amy
authors.initials: A
authors.lastname: Clemens-Smith
authors.forename: Ken H
authors.initials: KH
authors.lastname: Ho
authors.forename: Keith
authors.initials: K
authors.lastname: Jarvie
authors.forename: Geihan
authors.initials: G
authors.lastname: Rizkalla
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Wright
authors.forename: David O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: Darryle
authors.initials: D
authors.lastname: Schoepp
authors.forename: Edward L
authors.initials: EL
authors.lastname: Mattiuz
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stratford
authors.forename: Bryan
authors.initials: B
authors.lastname: Johnson
authors.forename: Craig
authors.initials: C
authors.lastname: Salhoff
authors.forename: Mary
authors.initials: M
authors.lastname: Katofiasc
authors.forename: Lee A
authors.initials: LA
authors.lastname: Phebus
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schenck
authors.forename: Marlene
authors.initials: M
authors.lastname: Cohen
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Filla
authors.forename: Paul L
authors.initials: PL
authors.lastname: Ornstein
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008881:Migraine Disorders / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010622:Phencyclidine / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D012501:Saphenous Vein / Q000166:cytology / Q000187:drug effects; D014162:Transfection
chemical_list: D001569:Benzodiazepines; D001798:Blood Proteins; D002118:Calcium; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D008024:Ligands; D010622:Phencyclidine; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C512994:6-((2-carboxy-4,4-difluoro-1-pyrrolidinyl)methyl)decahydro-3-isoquinolinecarboxylic acid; C079692:GYKI 53655