Clinical investigations of compounds targeting metabotropic glutamate receptors

Witkin, Jeffrey M.; Pandey, Kamal Prakash; Smith, Jodi L.

doi:10.1016/j.pbb.2022.173446

Cited by 23 publications

(14 citation statements)

References 240 publications

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“…A bioavailability study in mice shows that LBG30300 crosses the BBB and in combination with data from a FRET-based assay, leads us to conclude that LBG30300 is a promising candidate for development of an orthosteric mGlu 2 PET tracer. Such tool compounds are highly valuable for elucidating the correlation of mGlu subtype expression with diseases in the CNS. , …”

Section: Discussionmentioning

confidence: 99%

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,

Eshak,

Malhaire

et al. 2024

J. Med. Chem.

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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 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.

show abstract

Section: Discussionmentioning

confidence: 99%

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,

Eshak,

Malhaire

et al. 2024

J. Med. Chem.

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“…Targeting mGluRs has been considered a promising pharmacological strategy for treating neurodegenerative and neuropsychiatric diseases 31,33,74 . In addition to finetuning excitatory and inhibitory transmission, mGluRs have also been shown to play diverse regulatory roles in memory, neuronal development, and synaptic plasticity, of which the underlying mechanisms have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that targeting mGluRs is a promising pharmacological strategy for treating neurodegenerative and neuropsychiatric diseases 31,32 . Not only does the inhibition of group III mGluRs mediate hippocampal activity-dependent synaptic 5 / 32 plasticity 28 , but allosteric ligands of group III mGluRs also have shown proneurogenic effects [33][34][35][36] .…”

Section: Introductionmentioning

confidence: 99%

Targeting Metabotropic Glutamate Receptor 7 Promotes Neurogenesis

Zhao,

Wang,

Fang

et al. 2024

Preprint

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Human neural progenitor cells (hNPCs) have been reported to exist in various regions of the central nervous system (CNS) throughout the lifespan and to maintain homeostasis of the CNS. The endogenous NPC pools as well as their function decline during aging, neurodegeneration, or brain damage; therefore, supplementation with hNPCs or enhancement of the potency of endogenous NPCs could lead to potential treatments for these diseases. Here, we showed that 2-phospho-L-ascorbic acid (Asc-2P) promoted hNPC proliferation and differentiation by maintaining mitochondrial glycolysis under growth factor-lacking conditions. Upregulation of metabotropic glutamate receptor 7 (mGluR7) expression by Asc-2P treatment and retention of mGluR7 on the plasma membrane by the specific group III mGluR antagonist alpha-methylserine-O-phosphate (MSOP) promoted the formation of fibroblast growth factor receptor 1 (FGFR1) and mGluR7 complex on the cytomembrane, thereby enhanced the phosphorylation and activation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), maintained mitochondrial glycolysis, thus enhanced hNPC proliferation and differentiation in vitro and in vivo. Furthermore, Asc-2P treatment alleviated pathogenesis and related cognitive decline in an Alzheimer’s disease mouse model. Taken together, our findings indicated that modulation of mGluR7 by Asc-2P and/or its antagonists could be promising pharmaceutical and therapeutic options against neurodegeneration and related diseases.

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“…This result seems to be due to the fact that the substances target both pre-and postsynaptic segments of glutamate neurotransmission. Currently, the clinical use of glutamate metabotropic receptor ligands is limited [41]. Nevertheless, we believe that the fine modulation of glutamatergic synaptic transmission using mGluR ligands remains promising.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

Першина

Chernomorets

Fedorov

et al. 2023

IJMS

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We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.

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Clinical investigations of compounds targeting metabotropic glutamate receptors

Cited by 23 publications

References 240 publications

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

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

Targeting Metabotropic Glutamate Receptor 7 Promotes Neurogenesis

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

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Clinical investigations of compounds targeting metabotropic glutamate receptors

Cited by 23 publications

References 240 publications

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

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

Targeting Metabotropic Glutamate Receptor 7 Promotes Neurogenesis

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

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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

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