Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists
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Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists. / Staudt, Markus; Liu, Na; Malhaire, Fanny; Doroudian, Yasaman; Prézeau, Laurent; Renard, Emma; Hasanpour, Zahra; Pin, Jean Philippe; Bunch, Lennart.
In: European Journal of Medicinal Chemistry, Vol. 266, 116157, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists
AU - Staudt, Markus
AU - Liu, Na
AU - Malhaire, Fanny
AU - Doroudian, Yasaman
AU - Prézeau, Laurent
AU - Renard, Emma
AU - Hasanpour, Zahra
AU - Pin, Jean Philippe
AU - Bunch, Lennart
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024
Y1 - 2024
N2 - The metabotropic glutamate (Glu) receptors (mGluRs) are G-protein coupled receptors, which play a central role in modulating excitatory neurotransmission in the central nervous system (CNS). Thus, the development of tool compounds thereto, continues to interest the scientific community. In this study, we report the design and synthesis of new conformationally restricted 2-aminoadipic acid (2AA) 2–4, and glutamic acid 5, 6 analogs, which share the cyclopropane ring as the restrictor. The analogs were characterized at rat mGlu1−8 in an IP-One functional assay. While the 2AA analogs 3a, 4a and CCG-I analog 5a were shown to be selective mGlu2 agonists with low micromolar potencies, CCG-II analog 5b was shown to be a potent full agonist at mGlu2 (EC50 = 82 nM) with ∼15-fold selectivity over mGlu3, >25-fold selectivity over group III, and >60-fold selectivity over group I subtypes. An in silico study was performed to address this significant change (>3500 fold) in potency upon introduction of this methyl group (L-CCG-II vs 5b).
AB - The metabotropic glutamate (Glu) receptors (mGluRs) are G-protein coupled receptors, which play a central role in modulating excitatory neurotransmission in the central nervous system (CNS). Thus, the development of tool compounds thereto, continues to interest the scientific community. In this study, we report the design and synthesis of new conformationally restricted 2-aminoadipic acid (2AA) 2–4, and glutamic acid 5, 6 analogs, which share the cyclopropane ring as the restrictor. The analogs were characterized at rat mGlu1−8 in an IP-One functional assay. While the 2AA analogs 3a, 4a and CCG-I analog 5a were shown to be selective mGlu2 agonists with low micromolar potencies, CCG-II analog 5b was shown to be a potent full agonist at mGlu2 (EC50 = 82 nM) with ∼15-fold selectivity over mGlu3, >25-fold selectivity over group III, and >60-fold selectivity over group I subtypes. An in silico study was performed to address this significant change (>3500 fold) in potency upon introduction of this methyl group (L-CCG-II vs 5b).
U2 - 10.1016/j.ejmech.2024.116157
DO - 10.1016/j.ejmech.2024.116157
M3 - Journal article
C2 - 38245976
AN - SCOPUS:85182872784
VL - 266
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 116157
ER -
ID: 381497335