N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands

Rasmus Prætorius Clausen; Caspar Christensen; Kasper Bø Hansen; Jeremy R Greenwood; Lars Jørgensen; Nicola Micale; Jens Christian Madsen; Birgitte Nielsen; Jan Egebjerg; Hans Bräuner-Osborne; Stephen F Traynelis; Jesper Langgaard Kristensen

doi:10.1021/jm800025e

N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands

Rasmus Prætorius Clausen, Caspar Christensen, Kasper Bø Hansen, Jeremy R Greenwood, Lars Jørgensen, Nicola Micale, Jens Christian Madsen, Birgitte Nielsen, Jan Egebjerg, Hans Bräuner-Osborne, Stephen F Traynelis, Jesper Langgaard Kristensen

14 Citations (Scopus)

Abstract

A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	14
Pages (from-to)	4179-87
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm800025e
Publication status	Published - 2008

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Former Faculty of Pharmaceutical Sciences

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Clausen, R. P., Christensen, C., Hansen, K. B., Greenwood, J. R., Jørgensen, L., Micale, N., Madsen, J. C., Nielsen, B., Egebjerg, J., Bräuner-Osborne, H., Traynelis, S. F., & Kristensen, J. L. (2008). N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands. Journal of Medicinal Chemistry, 51(14), 4179-87. https://doi.org/10.1021/jm800025e

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title = "N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands",

abstract = "A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.",

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author = "Clausen, {Rasmus Pr{\ae}torius} and Caspar Christensen and Hansen, {Kasper B{\o}} and Greenwood, {Jeremy R} and Lars J{\o}rgensen and Nicola Micale and Madsen, {Jens Christian} and Birgitte Nielsen and Jan Egebjerg and Hans Br{\"a}uner-Osborne and Traynelis, {Stephen F} and Kristensen, {Jesper Langgaard}",

note = "Keywords: Animals; Chromatography, High Pressure Liquid; Circular Dichroism; Glycine; Ligands; Models, Molecular; Patch-Clamp Techniques; Receptors, N-Methyl-D-Aspartate; Xenopus",

year = "2008",

doi = "10.1021/jm800025e",

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pages = "4179--87",

journal = "Journal of Medicinal Chemistry",

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T1 - N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands

AU - Clausen, Rasmus Prætorius

AU - Christensen, Caspar

AU - Hansen, Kasper Bø

AU - Greenwood, Jeremy R

AU - Jørgensen, Lars

AU - Micale, Nicola

AU - Madsen, Jens Christian

AU - Nielsen, Birgitte

AU - Egebjerg, Jan

AU - Bräuner-Osborne, Hans

AU - Traynelis, Stephen F

AU - Kristensen, Jesper Langgaard

N1 - Keywords: Animals; Chromatography, High Pressure Liquid; Circular Dichroism; Glycine; Ligands; Models, Molecular; Patch-Clamp Techniques; Receptors, N-Methyl-D-Aspartate; Xenopus

PY - 2008

Y1 - 2008

N2 - A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.

AB - A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/jm800025e

DO - 10.1021/jm800025e

M3 - Journal article

C2 - 18578474

SN - 0022-2623

VL - 51

SP - 4179

EP - 4187

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 14

ER -

N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands

Abstract

Keywords

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