Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid

Möller, E; Egebjerg, Jan; Brehm, Lotte; Stensbøl, Tine B.; Johansen, Tommy N.; Madsen, Ulf; Krogsgaard‐Larsen, Povl

doi:10.1002/(sici)1520-636x(1999)11:10<752::aid-chir3>3.0.co;2-t

Cited by 33 publications

(31 citation statements)

References 40 publications

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“…agreement with previous studies (23 M) (31). Hill values of unity for all compounds indicate one homogeneous binding site population for both full-length iGluR5(Q) and iGluR5-S1S2.…”

Section: Resultssupporting

confidence: 92%

“…Domoic acid was obtained from Tocris Cookson (United Kingdom). (S)-ATPO was synthesized, purified, and resolved as previously described (30,31). The rat iGluR5-S1S2 construct was expressed and purified as previously reported (10).…”

Section: Methodsmentioning

confidence: 99%

“…ATPO was first described in its racemic form as a competitive AMPA receptor antagonist (30). Upon resolution of the ATPO enantiomers, a more detailed study was performed of the pharmacology on recombinant AMPA and kainic acid receptors expressed in Xenopus laevis oocytes (31). In these studies, (S)-ATPO was shown to be an antagonist at iGluR1-4 (K i values ranging from 2.0 to 6.7 M) and less potent at iGluR5 (K i ϭ 23 M), but no activity was observed at iGluR6 or KA2.…”

mentioning

confidence: 99%

“…In these studies, (S)-ATPO was shown to be an antagonist at iGluR1-4 (K i values ranging from 2.0 to 6.7 M) and less potent at iGluR5 (K i ϭ 23 M), but no activity was observed at iGluR6 or KA2. The R-enantiomer was virtually inactive at all subtypes (31). Important information on the binding mode of ATPO was obtained by determination of a crystal structure of (S)-ATPO in complex with the iGluR2 ligand-binding core (14).…”

mentioning

confidence: 99%

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Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

Hald

Naur

Pickering

et al. 2007

Journal of Biological Chemistry

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“…agreement with previous studies (23 M) (31). Hill values of unity for all compounds indicate one homogeneous binding site population for both full-length iGluR5(Q) and iGluR5-S1S2.…”

Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

Hald

Naur

Pickering

et al. 2007

Journal of Biological Chemistry

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“…UBP296 did not, however, have any appreciable activity at NMDA receptors (More et al, 2004). The antagonist derivative of ATPA, (S)-2-amino- 3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid, has been reported to be an antagonist at both GLU K5 and AMPA receptors, with a K i value of 23 M. (S)-2-Amino- 3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid was also reported to not significantly attenuate NMDA-mediated currents in the rat cortical wedge model (Møller et al, 1999). Another recently reported AMPA and kainate receptor antagonist, a 3-(5-tetrazolylmethoxy) analog of AMPA, inhibits GLU K5 receptors (IC 50 ϭ 131 Ϯ 4 M), but is 7-fold more potent at the GLU K2 /GLU K6 receptor (IC 50 ϭ 19 Ϯ 1 M), while also inhibiting AMPA receptors with IC 50 values ranging from 48 to 161 M (Frol- , 2005).…”

Section: Discussionmentioning

confidence: 99%

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

Weiss¹,

Alt²,

Ogden³

et al. 2006

J Pharmacol Exp Ther

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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

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GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

Madsen¹,

Bräuner‐Osborne²,

Greenwood³

et al. 2010

Pharmaceutical Sciences Encyclopedia

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The complex functions of the mammalian central nervous system (CNS) are primarily determined by ( S )‐glutamic acid (Glu) and 4‐aminobutyric acid (GABA), which hyperpolarizes neurons via multiple receptor subtypes. Glu can act as a neurotoxin and cause injury to neurons in neurological disorders, including reversal of Glu transporters. This article discusses functionality of GABA and glutamate receptor ligands, including their therapeutic potentials in CNS disorders.

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Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid

Cited by 33 publications

References 40 publications

Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

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

GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

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Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid

Cited by 33 publications

References 40 publications

Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

Pharmacological Characterization of the Competitive GLUK5 Receptor Antagonist Decahydroisoquinoline LY466195 in Vitro and in Vivo

GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

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