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 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2013

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

Résumé

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
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Dates et versions

hal-00803222 , version 1 (21-03-2013)

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  • HAL Id : hal-00803222 , version 1

Citer

Zeinab Assaf, Anja P. Larsen, Raminta Venskutonytė, Liwei Han, Bjarke Abrahamsen, et al.. 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. Journal of Medicinal Chemistry, 2013, 56, pp.1614-1628. ⟨hal-00803222⟩
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