Pharmacological Characterization of the Competitive GLU_K5 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), 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 M)-induced currents with an IC 50 value of 0.045 Ϯ 0.011 M. In HEK293 cells transfected with GLU K5 , GLU K2 /GLU K5 , or GLU K5 /GLU K6 receptors, LY466195 produced IC 50 values of 0.08 Ϯ 0.02, 0.34 Ϯ 0.17, and 0.07 Ϯ 0.02 M, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID 100 value of 100 g/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 g/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 g/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.Glutamate is the major excitatory neurotransmitter in the central nervous system and can act at three major types of ligand-gated ion channels that are defined by the activity of the subtype-selective agonists N-methyl-D-aspartate (NMDA), kainate, and ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (Collingridge and Lester, 1989). Five kainate receptors subtypes have been cloned and classified as either high-affinity (GLU K1 and GLU K2 ) or lowArticle, publication date, and citation information can be found at

Current and prospective pharmacological targets in relation to antimigraine action

“…Redrawn from Saxena and Tfelt-Hansen (2006) trigeminal ganglion or systemic administration of capsaicin, has allowed studies on the activation of the trigeminal system and its effects on the cranial vasculature (for review, see Arulmani et al 2006). This review also contains data on the ability of several drugs to inhibit plasma protein extravasation (e.g., Weiss et al 2006), although it should be kept in mind that extravasation inhibitors, such as CP-122,288 (Roon et al 2000), the neurokinin-1 receptor antagonist lanepitant (Goldstein et al 2001a;Goldstein et al 1997), and the mixed ET A /ET B receptor antagonist bosentan (May et al 1996) proved ineffective in the treatment of migraine. Thus, the relevance of plasma protein extravasation in migraine is no longer tenable (Peroutka 2005).…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…(Löscher et al, 1999). H͔kainate at human receptors expressed in HEK293 cells (Weiss et al, 2006). H͔kainate from human GluK3 expressed in HEK293 cells (Dolman et al, 2005 (Dolman et al, 2007).…”

“…H͔AMPA at human GluA3 expressed in HEK293 cells (Bleakman et al, 1999). H͔AMPA at human receptors expressed in HEK293 cells (Weiss et al, 2006). …”

“…Several classes of GluK1-selective antagonists designed from different templates include the decahydroisoquinolines (3S,4aR,6S,8aR)-6-((4-carboxyphenyl)methyl)-1,2, 3, 4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884) (Bortolotto et al, 1999) and 6-((2-carboxy-4, 4-difluoro-1-pyrrolidinyl)methyl)decahydro-3-isoquinolinecarboxylic acid (LY466195) (Weiss et al, 2006), and the 3-substituted phenylalanine analogs (Szymań ska et al, 2009) (Table 10). LY382884 is a competitive antagonist of heteromeric kainate receptors, including GluK1/ GluK2 and GluK1/GluK5, with similar potencies as at homomeric GluK1 (Bortolotto et al, 1999;Alt et al, 2004).…”

Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors

“…They contribute to excitatory postsynaptic transmission at some synapses, modulate excitatory and inhibitory neurotransmission from presynaptic loci, and modify network excitability through actions on neuronal ion channels (for reviews, see Lerma, 2006;Pinheiro and Mulle, 2006). Targeting KARs could be a useful strategy for therapy in several neurological diseases because antagonists are efficacious in animal models of epilepsy (Smolders et al, 2002), neuropathic and migraine pain (Filla et al, 2002;Weiss et al, 2006), and anxiety .…”