Stereocontrolled synthesis and pharmacological evaluation of azetidine-2,3-dicarboxylic acids at NMDA receptors
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Stereocontrolled synthesis and pharmacological evaluation of azetidine-2,3-dicarboxylic acids at NMDA receptors. / Sivaprakasam, Mangaleswaran; Hansen, Kasper Bø; David, Olivier; Nielsen, Birgitte; Traynelis, Stephen F; Clausen, Rasmus Prætorius; Couty, François; Bunch, Lennart.
In: ChemMedChem, Vol. 4, No. 1, 2009, p. 110-117.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Stereocontrolled synthesis and pharmacological evaluation of azetidine-2,3-dicarboxylic acids at NMDA receptors
AU - Sivaprakasam, Mangaleswaran
AU - Hansen, Kasper Bø
AU - David, Olivier
AU - Nielsen, Birgitte
AU - Traynelis, Stephen F
AU - Clausen, Rasmus Prætorius
AU - Couty, François
AU - Bunch, Lennart
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1002/cmdc.200800226
DO - 10.1002/cmdc.200800226
M3 - Journal article
C2 - 19009584
VL - 4
SP - 110
EP - 117
JO - Farmaco
JF - Farmaco
SN - 1860-7179
IS - 1
ER -
ID: 10243665