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

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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 languageEnglish
Pages (from-to)4179-4187
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number14
StatePublished - Jul 24 2008


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