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Author Notes:

Correspondence: Associate Professor Rasmus P. Clausen, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark, Phone: +45 35 33 65 66, Fax: +45 35 33 60 40, rac@farma.ku.dk.

Lars Skov and Michael Gajhede are acknowledged for their help with CD measurements. We thank Kimberly Haustein and Phuong Le for excellent technical assistance. We thank Drs. S. Heinemann (Salk Institute), S. Nakanishi (Kyoto University), and P. Seeburg (University of Heidelberg) for sharing cDNA encoding the NMDA receptor subunits. Tommy Liljefors is acknowledged for fruitful discussions on modeling and design.

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Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • PARTIAL AGONIST ACTION
  • GLUTAMATE RECEPTORS
  • BINDING CORE
  • CRYSTAL-STRUCTURES
  • NMDA RECEPTORS
  • IBOTENIC ACID
  • NR1 SUBUNIT
  • COMPLEX
  • INHIBITION
  • MECHANISMS

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

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Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 51, Number 14

Publisher:

, Pages 4179-4187

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2008 American Chemical Society.

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