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

• Type of Material: Article
• Authors: Mangaleswaran Sivaprakasam, Université de Versailles St-Quentin-en-Yvelines; Kasper B. Hansen, Emory University; Olivier David, Université de Versailles St-Quentin-en-Yvelines; Birgitte Nielsen, University of Copenhagen; Stephen Traynelis, Emory University; Rasmus P. Clausen, University of Copenhagen; François Couty, Université de Versailles St-Quentin-en-Yvelines; Lennart Bunch, University of Copenhagen
• Language: English
• Date: 2009-01-01
• Publisher: Wiley-VCH Verlag
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
• Final Published Version (URL): http://dx.doi.org/10.1002/cmdc.200800226
• Title of Journal or Parent Work: ChemMedChem
• ISSN: 1860-7179
• Volume: 4
• Issue: 1
• Start Page: 110
• End Page: 117
• Grant/Funding Information: 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: conformational restriction; PLASTICITY; AFFINITY; IBOTENIC ACID; NMDA; Chemistry, Medicinal; GLYCINE; PHARMACOLOGY & PHARMACY; receptors; AZETIDINIC AMINO-ACIDS; GLUTAMATE RECEPTORS; enantioselectivity; CHEMISTRY, MEDICINAL; Science & Technology; Life Sciences & Biomedicine; SUBUNIT; SUBTYPES; Pharmacology & Pharmacy; glutamate; LIGANDS
• Research Categories: Health Sciences, Pharmacology; Chemistry, Pharmaceutical

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.