Correction to Chemoenzymatic Synthesis of New 2,4-<i>syn</i>-Functionalized (<i>S</i>)‑Glutamate Analogues and Structure–Activity Relationship Studies at Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters

Correction to Chemoenzymatic Synthesis of New 2,4-<i>syn</i>-Functionalized (<i>S</i>)‑Glutamate Analogues and Structure–Activity Relationship Studies at Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporter

Chemoenzymatic Synthesis of New 2,4-<i>syn</i>-Functionalized (<i>S</i>)‑Glutamate Analogues and Structure–Activity Relationship Studies at Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters

In the mammalian central nervous system, (<i>S</i>)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-<i>syn</i>-Glu analogues <b>2b</b>–<b>p</b> is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone <b>3</b>. Pharmacological characterization at the iGluRs and EAAT1–3 subtypes revealed analogue <b>2i</b> as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue <b>2i</b> in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with <b>2i</b> comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with <b>2i</b>, similar to that of GluK3-LBD with glutamate bound

Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors

Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer’s disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1–3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with <i>K</i>_i of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (<i>K</i>_i of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function

(<i>S</i>)‑2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)­propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements and Structural and Biological Investigation

Starting from <b>1</b>–<b>4</b> and <b>7</b> structural templates, analogues based on bioisosteric replacements (<b>5a</b>–<b>c</b> vs <b>1</b>, <b>2</b> and <b>6</b> vs <b>7</b>) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with <b>2</b> and <b>5c</b> and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist <b>3</b> and antagonist <b>7</b> (2 mg/kg ip)