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Your search keyword '"Staudt, Markus"' showing total 4 results
Start Over Author "Staudt, Markus" Journal journal of medicinal chemistry
4 results on '"Staudt, Markus"'

1. 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

Author

Liu, Na, primary, Eshak, Floriane, additional, Malhaire, Fanny, additional, Brabet, Isabelle, additional, Prézeau, Laurent, additional, Renard, Emma, additional, Pin, Jean-Philippe, additional, Acher, Francine C., additional, Staudt, Markus, additional, and Bunch, Lennart, additional

Published
2024
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3. 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 mGlu2Receptor Agonist

Author

Liu, Na, Eshak, Floriane, Malhaire, Fanny, Brabet, Isabelle, Prézeau, Laurent, Renard, Emma, Pin, Jean-Philippe, Acher, Francine C., Staudt, Markus, and Bunch, Lennart

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). LBG30300was 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 LBG30300is a picomolar agonist at mGlu2with excellent selectivity over mGlu3and 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 LBG30300which 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 mGlu2and mGlu3and thus could explain the observed subtype selectivity.

Published
2024
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4. Design, Synthesis, Pharmacology, and In Silico Studies of (1 S ,2 S ,3 S )-2-(( S )-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu 2 Receptor Agonist.

Author

Liu N, Eshak F, Malhaire F, Brabet I, Prézeau L, Renard E, Pin JP, Acher FC, Staudt M, and Bunch L

Subjects
Mice, Animals, Cyclopropanes pharmacology, Excitatory Amino Acid Agonists pharmacology, Glutamates, Carboxylic Acids, Central Nervous System metabolism, Receptors, Metabotropic Glutamate metabolism
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 (1 S ,2 S ,3 S )-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 mGlu 2 with excellent selectivity over mGlu 3 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 mGlu 2 and mGlu 3 and thus could explain the observed subtype selectivity.

Published
2024
Full Text
View/download PDF

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