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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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
JournalJournal of Medicinal Chemistry
Volume51
Issue number14
Pages (from-to)4179-87
ISSN0022-2623
DOIs
Publication statusPublished - 2008

Bibliographical note

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

ID: 9511537