title: Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
abstract: In the mammalian central nervous system, (S)-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-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen Ø, Denmark.
authors: Zeinab
authors: Z
authors: Assaf
authors: Anja P
authors: AP
authors: Larsen
authors: Raminta
authors: R
authors: Venskutonytė
authors: Liwei
authors: L
authors: Han
authors: Bjarke
authors: B
authors: Abrahamsen
authors: Birgitte
authors: B
authors: Nielsen
authors: Michael
authors: M
authors: Gajhede
authors: Jette S
authors: JS
authors: Kastrup
authors: Anders A
authors: AA
authors: Jensen
authors: Darryl S
authors: DS
authors: Pickering
authors: Karla
authors: K
authors: Frydenvang
authors: Thierry
authors: T
authors: Gefflaut
authors: Lennart
authors: L
authors: Bunch
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D002384:Catalysis; D018360:Crystallography, X-Ray; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007656:Ketoglutaric Acids / Q000138:chemical synthesis / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism; D058468:Receptors, Ionotropic Glutamate / Q000737:chemistry / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000097808:GluK3 Kainate Receptor
chemical_list: D001219:Aspartate Aminotransferases; D050491:Glutamate Plasma Membrane Transport Proteins; D005971:Glutamates; D018698:Glutamic Acid; D007656:Ketoglutaric Acids; D008024:Ligands; D018091:Receptors, AMPA; D058468:Receptors, Ionotropic Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D000097808:GluK3 Kainate Receptor; C582541:(2S,4R)-4-(3-hydroxy(methyl)amino-3-oxopropyl)glutamic Acid; C104722:glutamate receptor ionotropic, AMPA 2