TY - JOUR
T1 - Azetidinic amino acids
T2 - stereocontrolled synthesis and pharmacological characterization as ligands for glutamate receptors and transporters
AU - Bräuner-Osborne, Hans
AU - Bunch, Lennart
AU - Chopin, Nathalie
AU - Couty, François
AU - Evano, Gwilherm
AU - Jensen, Anders A.
AU - Kusk, Mie Lindskov
AU - Nielsen, Birgitte
AU - Rabasso, Nicolas
PY - 2005
Y1 - 2005
N2 - A set of ten azetidinic amino acids, that can be envisioned as C-4 alkyl substituted analogues of trans-2-carboxyazetidine-3-acetic acid (t-CAA) and/or conformationally constrained analogues of (R)- or (S)-glutamic acid (Glu) have been synthesized in a diastereo- and enantiomerically pure form from beta-amino alcohols through a straightforward five step sequence. The key step of this synthesis is an original anionic 4-exo-tet ring closure that forms the azetidine ring upon an intramolecular Michael addition. This reaction was proven to be reversible and to lead to a thermodynamic distribution of two diastereoisomers that were easily separated and converted in two steps into azetidinic amino acids. Azetidines 35-44 were characterized in binding studies on native ionotropic Glu receptors and in functional assays at cloned metabotropic receptors mGluR1, 2 and 4, representing group I, II and III mGlu receptors, respectively. Furthermore, azetidine analogues 35, 36, and 40 were also characterized as potential ligands at the glutamate transporter subtypes EAAT1-3 in the FLIPR Membrane Potential (FMP) assay. The (2R)-azetidines 35, 37, 39, 41 and 43 were inactive in iGlu, mGlu and EAAT assays, whereas a marked change in the pharmacological profile at the iGlu receptors was observed when a methyl group was introduced in the C-4 position, compound 36 versus t-CAA. At EAAT1-3, compound 35 was inactive, whereas azetidines 36 and 40 were both identified as inhibitors and showed selectivity for the EAAT2 subtype.
AB - A set of ten azetidinic amino acids, that can be envisioned as C-4 alkyl substituted analogues of trans-2-carboxyazetidine-3-acetic acid (t-CAA) and/or conformationally constrained analogues of (R)- or (S)-glutamic acid (Glu) have been synthesized in a diastereo- and enantiomerically pure form from beta-amino alcohols through a straightforward five step sequence. The key step of this synthesis is an original anionic 4-exo-tet ring closure that forms the azetidine ring upon an intramolecular Michael addition. This reaction was proven to be reversible and to lead to a thermodynamic distribution of two diastereoisomers that were easily separated and converted in two steps into azetidinic amino acids. Azetidines 35-44 were characterized in binding studies on native ionotropic Glu receptors and in functional assays at cloned metabotropic receptors mGluR1, 2 and 4, representing group I, II and III mGlu receptors, respectively. Furthermore, azetidine analogues 35, 36, and 40 were also characterized as potential ligands at the glutamate transporter subtypes EAAT1-3 in the FLIPR Membrane Potential (FMP) assay. The (2R)-azetidines 35, 37, 39, 41 and 43 were inactive in iGlu, mGlu and EAAT assays, whereas a marked change in the pharmacological profile at the iGlu receptors was observed when a methyl group was introduced in the C-4 position, compound 36 versus t-CAA. At EAAT1-3, compound 35 was inactive, whereas azetidines 36 and 40 were both identified as inhibitors and showed selectivity for the EAAT2 subtype.
KW - Amino Acid Transport System X-AG
KW - Amino Acids
KW - Animals
KW - Azetidines
KW - Cyclization
KW - Humans
KW - Ligands
KW - Protein Binding
KW - Receptors, Glutamate
KW - Receptors, Metabotropic Glutamate
KW - Stereoisomerism
KW - Structure-Activity Relationship
U2 - 10.1039/b509514j
DO - 10.1039/b509514j
M3 - Journal article
C2 - 16240010
SN - 1470-4358
VL - 3
SP - 3926
EP - 3936
JO - Journal of the Chemical Society, Perkin Transactions 1
JF - Journal of the Chemical Society, Perkin Transactions 1
IS - 21
ER -