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1.
Neuropharmacology ; 140: 275-286, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30102917

RESUMO

Due to the essential roles of glutamate, detection and response to a large range of extracellular concentrations of this excitatory amino acid are necessary for the fine-tuning of brain functions. Metabotropic glutamate receptors (mGluRs) are implicated in shaping the activity of many synapses in the central nervous system. Among the eight mGluR subtypes, there is increasing interest in studying the mGlu3 receptor which has recently been linked to various diseases, including psychiatric disorders. This receptor displays striking functional properties, with a high and, often, full basal activity, making its study elusive in heterologous systems. Here, we demonstrate that Cl- ions exert strong positive allosteric modulation of glutamate on the mGlu3 receptor. We have also identified the molecular and structural determinants lying behind this allostery: a unique interactive "chloride-lock" network. Indeed, Cl- ions dramatically stabilize the glutamate-induced active state of the extracellular domain of the mGlu3 receptor. Thus, the mGlu3 receptors' large basal activity does not correspond to a constitutive activity in absence of agonist. Instead, it results mostly from a Cl-mediated amplified response to low ambient glutamate concentrations, such as those measured in cell media. This strong interaction between glutamate and Cl- ions allows the mGlu3 receptor to sense and efficiently react to sub-micromolar concentrations of glutamate, making it the most sensitive member of mGluR family.


Assuntos
Cloretos/metabolismo , Ácido Glutâmico/metabolismo , Receptores de AMPA/agonistas , Receptores de AMPA/metabolismo , Regulação Alostérica , Sítios de Ligação/efeitos dos fármacos , Células Cultivadas , Cloretos/farmacologia , Humanos , Inosina Monofosfato/metabolismo , Medições Luminescentes , Mutação , Ensaio Radioligante
2.
J Med Chem ; 61(5): 1969-1989, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29397723

RESUMO

A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.


Assuntos
Sítios de Ligação , Receptores de Glutamato Metabotrópico/agonistas , Aminobutiratos/farmacologia , Animais , Ácido Glutâmico/química , Humanos , Ligantes , Modelos Moleculares , Mimetismo Molecular , Ácidos Fosfínicos/farmacologia , Células de Purkinje/ultraestrutura , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
3.
J Med Chem ; 59(3): 914-24, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26814576

RESUMO

The metabotropic glutamate (Glu) receptors (mGluRs) play key roles in modulating excitatory neurotransmission in the brain. In all, eight subtypes have been identified and divided into three groups, group I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6-8). In this article, we present a L-2,4-syn-substituted Glu analogue, 1d, which displays selective agonist activity at mGlu2 over the remaining mGluR subtypes. A modeling study and redesign of the core scaffold led to the stereoselective synthesis of four new conformationally restricted Glu analogues, 2a-d. Most interestingly, 2a retained a selective agonist activity profile at mGlu2 (EC50 in the micromolar range), whereas 2c/2d were both selective agonists at group III, subtypes mGlu4,6,8. In general, 2d was 20-fold more potent than 2c and potently activated mGlu4,6,8 in the low-mid nanomolar range.


Assuntos
Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Animais , Células Cultivadas , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ácido Glutâmico/síntese química , Ácido Glutâmico/química , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
4.
FASEB J ; 29(10): 4174-88, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26116702

RESUMO

Metabotropic glutamate receptors (mGluRs) play key roles in the modulation of many synapses. Chloride (Cl(-)) is known to directly bind and regulate the function of different actors of neuronal activity, and several studies have pointed to the possible modulation of mGluRs by Cl(-). Herein, we demonstrate that Cl(-) behaves as a positive allosteric modulator of mGluRs. For example, whereas glutamate potency was 3.08 ± 0.33 µM on metabotropic glutamate (mGlu) 4 receptors in high-Cl(-) buffer, signaling activity was almost abolished in low Cl(-) in cell-based assays. Cl(-) potency was 78.6 ± 3.5 mM. Cl(-) possesses a high positive cooperativity with glutamate (Hill slope ≈6 on mGlu4), meaning that small variations in [Cl(-)] lead to large variations in glutamate action. Using molecular modeling and mutagenesis, we have identified 2 well-conserved Cl(-) binding pockets in the extracellular domain of mGluRs. Moreover, modeling of activity-dependent Cl(-) variations at GABAergic synapses suggests that these variations may be compatible with a dynamic modulation of the most sensitive mGluRs present in these synapses. Taken together, these data reveal a necessary role of Cl(-) for the glutamate activation of many mGluRs. Exploiting Cl(-) binding pockets may yield to the development of innovative regulators of mGluR activity.


Assuntos
Cloretos/metabolismo , Espaço Extracelular/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Sítio Alostérico , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Cloretos/farmacologia , Células HEK293 , Humanos , Modelos Moleculares , Mutação , Ligação Proteica , Estrutura Terciária de Proteína/efeitos dos fármacos , Ratos , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Homologia de Sequência de Aminoácidos
5.
Bioorg Med Chem Lett ; 25(12): 2523-6, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25958247

RESUMO

The four stereoisomers of 1-amino-2-fluoro-2-(phosphonomethyl)cyclopropane-1-carboxylic acid (FAP4) were synthesized via diastereoselective Rh(II)-catalysed cyclopropanation of a phosphonylated fluoroalkene. Different isomers of FAP4 and the corresponding non-fluorinated analogs showed a similar pharmacological profile against the isoforms of metabotropic glutamate receptor (mGluR). Within the fluorinated series, (-)-(Z)-FAP4 and (-)-(E)-FAP4 demonstrated the highest agonist activity against mGlu4 (EC50 0.10 µM). Our results suggest that fluorocyclopropanes bearing an amino-acid function can be suitable for the development of potent conformationally restricted mGluR agonists.


Assuntos
Ácidos Carboxílicos/química , Receptores de Glutamato Metabotrópico/agonistas , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/metabolismo , Ciclopropanos/química , Ácido Glutâmico/química , Ácido Glutâmico/metabolismo , Ligação Proteica , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Estereoisomerismo
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