N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands. / Clausen, Rasmus Prætorius; Christensen, Caspar; Hansen, Kasper Bø; Greenwood, Jeremy R; Jørgensen, Lars; Micale, Nicola; Madsen, Jens Christian; Nielsen, Birgitte; Egebjerg, Jan; Bräuner-Osborne, Hans; Traynelis, Stephen F; Kristensen, Jesper Langgaard.
I: Journal of Medicinal Chemistry, Bind 51, Nr. 14, 2008, s. 4179-87.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
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
VL - 51
SP - 4179
EP - 4187
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -
ID: 9511537