Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu2 Receptor Agonist
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Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300) : A Picomolar Potency Subtype-Selective mGlu2 Receptor Agonist. / Liu, Na; Eshak, Floriane; Malhaire, Fanny; Brabet, Isabelle; Prézeau, Laurent; Renard, Emma; Pin, Jean Philippe; Acher, Francine C.; Staudt, Markus; Bunch, Lennart.
In: Journal of Medicinal Chemistry, Vol. 67, No. 2, 2024, p. 1314–1326.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300)
T2 - A Picomolar Potency Subtype-Selective mGlu2 Receptor Agonist
AU - Liu, Na
AU - Eshak, Floriane
AU - Malhaire, Fanny
AU - Brabet, Isabelle
AU - Prézeau, Laurent
AU - Renard, Emma
AU - Pin, Jean Philippe
AU - Acher, Francine C.
AU - Staudt, Markus
AU - Bunch, Lennart
N1 - Publisher Copyright: © 2024 American Chemical Society.
PY - 2024
Y1 - 2024
N2 - Metabotropic glutamate (Glu) receptors (mGlu receptors) play a key role in modulating excitatory neurotransmission in the central nervous system (CNS). In this study, we report the structure-based design and pharmacological evaluation of densely functionalized, conformationally restricted glutamate analogue (1S,2S,3S)-2-((S)-amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic acid (LBG30300). LBG30300 was synthesized in a stereocontrolled fashion in nine steps from a commercially available optically active epoxide. Functional characterization of all eight mGlu receptor subtypes showed that LBG30300 is a picomolar agonist at mGlu2 with excellent selectivity over mGlu3 and the other six mGlu receptor subtypes. Bioavailability studies on mice (IV administration) confirm CNS exposure, and an in silico study predicts a binding mode of LBG30300 which induces a flipping of Tyr144 to allow for a salt bridge interaction of the acetate group with Arg271. The Tyr144 residue now prevents Arg271 from interacting with Asp146, which is a residue of differentiation between mGlu2 and mGlu3 and thus could explain the observed subtype selectivity.
AB - Metabotropic glutamate (Glu) receptors (mGlu receptors) play a key role in modulating excitatory neurotransmission in the central nervous system (CNS). In this study, we report the structure-based design and pharmacological evaluation of densely functionalized, conformationally restricted glutamate analogue (1S,2S,3S)-2-((S)-amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic acid (LBG30300). LBG30300 was synthesized in a stereocontrolled fashion in nine steps from a commercially available optically active epoxide. Functional characterization of all eight mGlu receptor subtypes showed that LBG30300 is a picomolar agonist at mGlu2 with excellent selectivity over mGlu3 and the other six mGlu receptor subtypes. Bioavailability studies on mice (IV administration) confirm CNS exposure, and an in silico study predicts a binding mode of LBG30300 which induces a flipping of Tyr144 to allow for a salt bridge interaction of the acetate group with Arg271. The Tyr144 residue now prevents Arg271 from interacting with Asp146, which is a residue of differentiation between mGlu2 and mGlu3 and thus could explain the observed subtype selectivity.
U2 - 10.1021/acs.jmedchem.3c01811
DO - 10.1021/acs.jmedchem.3c01811
M3 - Journal article
C2 - 38170918
AN - SCOPUS:85182005459
VL - 67
SP - 1314
EP - 1326
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 2
ER -
ID: 380203867