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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. rac@farma.ku.dk
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Caspar
authors.initials: C
authors.lastname: Christensen
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Greenwood
authors.forename: Lars
authors.initials: L
authors.lastname: Jørgensen
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Jens Christian
authors.initials: JC
authors.lastname: Madsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Jan
authors.initials: J
authors.lastname: Egebjerg
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D014981:Xenopus
chemical_list: D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine