N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands.
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.
Clausen
Rasmus P
RP
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. rac@farma.ku.dk
Christensen
Caspar
C
Hansen
Kasper B
KB
Greenwood
Jeremy R
JR
Jørgensen
Lars
L
Micale
Nicola
N
Madsen
Jens Christian
JC
Nielsen
Birgitte
B
Egebjerg
Jan
J
Bräuner-Osborne
Hans
H
Traynelis
Stephen F
SF
Kristensen
Jesper L
JL
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
D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine