Azetidinic amino acids: stereocontrolled synthesis and pharmacological characterization as ligands for glutamate receptors and transporters
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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.
Original language | English |
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Journal | Organic & Biomolecular Chemistry |
Volume | 3 |
Issue number | 21 |
Pages (from-to) | 3926-36 |
Number of pages | 11 |
ISSN | 1477-0520 |
DOIs | |
Publication status | Published - 2005 |
- Amino Acid Transport System X-AG, Amino Acids, Animals, Azetidines, Cyclization, Humans, Ligands, Protein Binding, Receptors, Glutamate, Receptors, Metabotropic Glutamate, Stereoisomerism, Structure-Activity Relationship
Research areas
ID: 38484797