The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

Clausen, Rasmus P.; Hansen, Kasper B.; Calí, Patrizia; Nielsen, Birgitte; Greenwood, Jeremy R.; Begtrup, Mikael; Egebjerg, Jan; Bräuner‐Osborne, Hans

doi:10.1016/j.ejphar.2004.07.049

Cited by 22 publications

(37 citation statements)

References 31 publications

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“…Affinities for native AMPA, KA, and NMDA receptors in rat cortical synaptosomes were determined using 5 nM (RS)- (30), respectively, with minor modifications as previously described (31,32).…”

Section: Pharmacologymentioning

confidence: 99%

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Larsen

Venskutonytė

Valadés

et al. 2010

ACS Chem. Neurosci.

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The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K b of 11.4 μM.

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Section: Pharmacologymentioning

confidence: 99%

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Larsen

Venskutonytė

Valadés

et al. 2010

ACS Chem. Neurosci.

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“…The collected fractions of the first eluting peak were pooled, evaporated, re-evaporated three times from water, and dried in vacuo to give (-)-15 (mp 176-177°C dec). Yield (122 mg, 98% (17). Triflic anhydride (2.22 mL, 13.42 mmol) was added to a solution of 16 (3.00 g, 11.18 mmol) and 2,6-lutidine (1.56 mL, 13.42 mmol) in dry dichloromethane (60 mL) cooled (-45°C) under inert atmosphere.…”

Section: Methodsmentioning

confidence: 99%

“…26 Affinities for native AMPA, KA, and NMDA receptors were determined using 5 nM [ 29 respectively, with minor modifications as previously described. 17 Nonspecific binding was determined using 1 mM (S)-Glu. Data were analyzed using GraphPad Prism, version 4.0 (GraphPad Software Inc., San Diego, CA) and fit to the equation…”

Section: Articlementioning

confidence: 99%

4-Hydroxy-1,2,5-oxadiazol-3-yl Moiety as Bioisoster of the Carboxy Function. Synthesis, Ionization Constants, and Molecular Pharmacological Characterization at Ionotropic Glutamate Receptors of Compounds Related to Glutamate and Its Homologues

Lolli

Giordano²,

Pickering³

et al. 2010

J. Med. Chem.

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In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic R-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (þ)-10, was an unselective, though potent AMPA receptor preferring agonist (EC 50 = 10 μM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (þ)-15 and (þ)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.

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“…The racemic mixture of 2-(N-hydroxypyrazol-4-yl)glycine was synthesized as described previously (Cali and Begtrup, 2002;Clausen et al, 2004) and enantiomers separated with a CR(ϩ) Crownpak column (150 ϫ 10 mm) using 0.1% aqueous trifluoroacetic acid as eluent. D-Cysteic acid was prepared from D-cysteine as described previously (Darkwa et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

Subunit-Specific Agonist Activity at NR2A-, NR2B-, NR2C-, and NR2D-ContainingN-Methyl-d-aspartate Glutamate Receptors

et al. 2007

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The four N-methyl-D-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A-and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.NMDA receptors are ligand-gated ion channels that mediate a component of excitatory synaptic transmission that can trigger changes in synaptic strength (Malenka and Nicoll, 1993). NMDA receptors have also been implicated in the pathophysiology of stroke and brain injury (Wang and Shuaib, 2005), epilepsy (Mares et al., 2004), as well as a range of psychiatric disorders (Heresco-Levy and Javitt, 1998;MacDonald and Chafee, 2006). NMDA receptors are tetrameric protein complexes composed of a combination of glycine-binding NR1 subunits and glutamate-binding NR2 subunits (Dingledine et al., 1999;Chen and Wyllie, 2006).

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The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

Cited by 22 publications

References 31 publications

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

4-Hydroxy-1,2,5-oxadiazol-3-yl Moiety as Bioisoster of the Carboxy Function. Synthesis, Ionization Constants, and Molecular Pharmacological Characterization at Ionotropic Glutamate Receptors of Compounds Related to Glutamate and Its Homologues

Subunit-Specific Agonist Activity at NR2A-, NR2B-, NR2C-, and NR2D-ContainingN-Methyl-d-aspartate Glutamate Receptors

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