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Author Notes:

Email: François Couty Prof. (couty@chimie.uvsq.fr), Lennart Bunch Prof. (lebu@farma.ku.dk)

Subjects:

Research Funding:

We would like to thank the Carlsberg Foundation, the Alfred Benzon Foundation, the Villum Kann Rasmussen Foundation, the Lundbeck Foundation, the Danish Medical Research Council, NIH-NINDS (NS36654), and IFCPAR (Indo-French Center for the Promotion of Advanced Research) is gratefully acknowledged for funding (Project N°3005-1).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • CHEMISTRY, MEDICINAL
  • PHARMACOLOGY & PHARMACY
  • conformational restriction
  • enantioselectivity
  • glutamate
  • NMDA
  • receptors
  • AZETIDINIC AMINO-ACIDS
  • GLUTAMATE RECEPTORS
  • IBOTENIC ACID
  • LIGANDS
  • SUBUNIT
  • PLASTICITY
  • AFFINITY
  • SUBTYPES
  • GLYCINE

Stereocontrolled Synthesis and Pharmacological Evaluation of Azetidine-2,3-Dicarboxylic Acids at NMDA Receptors

Tools:

Journal Title:

ChemMedChem

Volume:

Volume 4, Number 1

Publisher:

, Pages 110-117

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The four stereoisomers of azetidine-2,3-dicaroxylic acid (L-trans-ADC, L-cis-ADC, D-trans-ADC, and D-cis-ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis-ADC enantiomers and one giving access to the two trans-ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([ 3H]CGP39653) at native NMDA receptors: L-trans-ADC showed the highest affinity (Ki = 70 μM) followed by the D-cis-ADC stereoisomer (21 μM). In contrast, the two analogues L-cis-ADC and d-trans-ADC were low-affinity ligands (> 700 and 90μM, respectively). Electrophysiological characterization of the ADC com-pounds at the four NMDA receptor subtypes NR7/NR2A, NR1/NR2B, NR1/NR2C, and NR7/NR2D expressed in Xenopus oocytes showed that L-trans-ADC displayed the highest agonist potency at NR1/NR2D (EC 50 = 50μM), which was 9.4-, 3.4-, and 7.9-fold higher than the respective potencies at NR7/NR2A-C. D-cis-ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium-range micromolar potencies (EC50 = 720 and 230 μm, respectively). A subsequent in silico ligand-protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site.

Copyright information:

© 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

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