title: Stereocontrolled synthesis and pharmacological evaluation of azetidine-2,3-dicarboxylic acids at NMDA receptors.
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 ([(3)H]CGP39653) at native NMDA receptors: L-trans-ADC showed the highest affinity (K(i)=10 microM) followed by the D-cis-ADC stereoisomer (21 microM). In contrast, the two analogues L-cis-ADC and D-trans-ADC were low-affinity ligands (>100 and 90 microM, respectively). Electrophysiological characterization of the ADC compounds at the four NMDA receptor subtypes NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D expressed in Xenopus oocytes showed that L-trans-ADC displayed the highest agonist potency at NR1/NR2D (EC(50)=50 microM), which was 9.4-, 3.4-, and 1.9-fold higher than the respective potencies at NR1/NR2A-C. D-cis-ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium-range micromolar potencies (EC(50)=720 and 230 microM, respectively). A subsequent in silico ligand-protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site.
authors.affiliation: UniverSud Paris, Institut Lavoisier de Versailles, UMR CNRS 8081, Université de Versailles St-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France.
authors.forename: Mangaleswaran
authors.initials: M
authors.lastname: Sivaprakasam
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Olivier
authors.initials: O
authors.lastname: David
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: François
authors.initials: F
authors.lastname: Couty
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009865:Oocytes / Q000187:drug effects; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D003998:Dicarboxylic Acids; D016194:Receptors, N-Methyl-D-Aspartate; C538898:azetidine-2,3-dicarboxylic acid; D001383:Azetidinecarboxylic Acid