Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7.
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Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7. / Sagot, Emanuelle; Pickering, Darryl S; Pu, Xiaosui; Umberti, Michelle; Stensbøl, Tine B; Nielsen, Birgitte; Chapelet, Marion; Bolte, Jean; Gefflaut, Thierry; Bunch, Lennart.
In: Journal of Medicinal Chemistry, Vol. 51, No. 14, 2008, p. 4093-103.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7.
AU - Sagot, Emanuelle
AU - Pickering, Darryl S
AU - Pu, Xiaosui
AU - Umberti, Michelle
AU - Stensbøl, Tine B
AU - Nielsen, Birgitte
AU - Chapelet, Marion
AU - Bolte, Jean
AU - Gefflaut, Thierry
AU - Bunch, Lennart
N1 - Keywords: Amination; Animals; Glutamic Acid; Magnetic Resonance Spectroscopy; Mass Spectrometry; Rats; Receptors, Glutamate; Spectrophotometry, Infrared; Structure-Activity Relationship; Synaptosomes
PY - 2008
Y1 - 2008
N2 - ( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.
AB - ( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/jm800092x
DO - 10.1021/jm800092x
M3 - Journal article
C2 - 18578478
VL - 51
SP - 4093
EP - 4103
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -
ID: 6747815