Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3
Research output: Contribution to journal › Journal article › Research › peer-review
The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.
Original language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 49 |
Issue number | 1 |
Pages (from-to) | 172-8 |
Number of pages | 7 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 2006 |
- Animals, Bicyclo Compounds, Heterocyclic, Binding Sites, Cell Line, Dicarboxylic Acids, Drug Design, Excitatory Amino Acid Transporter 1, Excitatory Amino Acid Transporter 3, Glutamate Plasma Membrane Transport Proteins, Humans, Models, Molecular, Molecular Conformation, Rats, Receptors, Glutamate, Stereoisomerism, Structure-Activity Relationship
Research areas
ID: 38484728