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.
Original language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 51 |
Issue number | 14 |
Pages (from-to) | 4179-87 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 2008 |
Bibliographical note
Keywords: Animals; Chromatography, High Pressure Liquid; Circular Dichroism; Glycine; Ligands; Models, Molecular; Patch-Clamp Techniques; Receptors, N-Methyl-D-Aspartate; XenopusKeywords
- Former Faculty of Pharmaceutical Sciences