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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

Harvard

Liu, N, Eshak, F, Malhaire, F, Brabet, I, Prézeau, L, Renard, E, Pin, JP, Acher, FC, Staudt, M & Bunch, L 2024, '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', Journal of Medicinal Chemistry, vol. 67, no. 2, pp. 1314–1326. https://doi.org/10.1021/acs.jmedchem.3c01811

APA

Liu, N., Eshak, F., Malhaire, F., Brabet, I., Prézeau, L., Renard, E., Pin, J. P., Acher, F. C., Staudt, M., & Bunch, L. (2024). 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. Journal of Medicinal Chemistry, 67(2), 1314–1326. https://doi.org/10.1021/acs.jmedchem.3c01811

Vancouver

Liu N, Eshak F, Malhaire F, Brabet I, Prézeau L, Renard E et al. 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. Journal of Medicinal Chemistry. 2024;67(2):1314–1326. https://doi.org/10.1021/acs.jmedchem.3c01811

Author

Liu, Na ; Eshak, Floriane ; Malhaire, Fanny ; Brabet, Isabelle ; Prézeau, Laurent ; Renard, Emma ; Pin, Jean Philippe ; Acher, Francine C. ; Staudt, Markus ; Bunch, Lennart. / 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. In: Journal of Medicinal Chemistry. 2024 ; Vol. 67, No. 2. pp. 1314–1326.

Bibtex

@article{86b4d741e3224a08a73466219c2bfb63,
title = "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",
abstract = "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.",
author = "Na Liu and Floriane Eshak and Fanny Malhaire and Isabelle Brabet and Laurent Pr{\'e}zeau and Emma Renard and Pin, {Jean Philippe} and Acher, {Francine C.} and Markus Staudt and Lennart Bunch",
note = "Publisher Copyright: {\textcopyright} 2024 American Chemical Society.",
year = "2024",
doi = "10.1021/acs.jmedchem.3c01811",
language = "English",
volume = "67",
pages = "1314–1326",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

}

RIS

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