Chemoenzymatic Synthesis of New 2,4-syn-Functionalized (S)-Glutamate Analogues and Structure鈥揂ctivity Relationship Studies at Ionotropic Glutamate Receptors and Excitatory Amino Acid Tra
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- 作者：Zeinab Assaf ; Anja P. Larsen ; Raminta Venskutonyt臈 ; Liwei Han ; Bjarke Abrahamsen ; Birgitte Nielsen ; Michael Gajhede ; Jette S. Kastrup ; Anders A. Jensen ; Darryl S. Pickering ; Karla Frydenvang ; Thierry Gefflaut ; Lennart Bunch
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 28, 2013
- 年：2013
- 卷：56
- 期：4
- 页码：1614-1628
- 全文大小：625K
- 年卷期：v.56,no.4(February 28, 2013)
- ISSN：1520-4804
文摘
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鈥?b>p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1鈥? 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.