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.
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.
Bunch
Lennart
L
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark. lebu@dfuni.dk
Nielsen
Birgitte
B
Jensen
Anders A
AA
Bräuner-Osborne
Hans
H
D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors*; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3 / Q000037:antagonists & inhibitors*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C507815:3-azabicyclo(3.3.0)octane-4,6-dicarboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003998:Dicarboxylic Acids; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D017470:Receptors, Glutamate; C493400:SLC1A1 protein, human; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human