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

• Type of Material: Article
• Authors: Rasmus P. Clausen, University of Copenhagen; Caspar Christensen, University of Copenhagen; Kasper B. Hansen, Emory University; Jeremy R. Greenwood, University of Copenhagen; Lars Jørgensen, University of Copenhagen; Nicola Micale, University of Copenhagen; Jens Christian Madsen, H. Lundbeck A/S; Birgitte Nielsen, University of Copenhagen; Jan Egebjerg, H. Lundbeck A/S; Hans Bräuner-Osborne, University of Copenhagen; Stephen Traynelis, Emory University; Jesper L. Kristensen, University of Copenhagen
• Language: English
• Date: 2008-07-24
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/jm800025e
• Title of Journal or Parent Work: Journal of Medicinal Chemistry
• ISSN: 0022-2623
• Volume: 51
• Issue: 14
• Start Page: 4179
• End Page: 4187
• Grant/Funding Information: This work was supported by NIH (SFT), the Carlsberg Foundation (CC), the Alfred Benzon Foundation (KBH), Villum Kann Rasmussen Foundation (KBH), the Lundbeck Foundation (KBH), the Drug Research Academy (NM) and the Augustinus Foundation (HBO).
• Keywords: NR1 SUBUNIT; COMPLEX; IBOTENIC ACID; Life Sciences & Biomedicine; INHIBITION; NMDA RECEPTORS; MECHANISMS; Science & Technology; PARTIAL AGONIST ACTION; GLUTAMATE RECEPTORS; Pharmacology & Pharmacy; BINDING CORE; Chemistry, Medicinal; CRYSTAL-STRUCTURES
• Research Categories: Health Sciences, Pharmacology; Chemistry, Pharmaceutical

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.