RESUMO
Protons act as neuromodulators and produce significant effects on synaptic transmission. The molecular basis of neuromodulation by extracellular protons is partially explained by their effects on certain neurotransmitter receptors and ion channels. The metabotropic glutamate receptors (mGluRs) are a family of eight receptor subtypes that are widely expressed throughout the mammalian CNS. In this study, the effects of physiologically relevant changes in extracellular pH were examined in mammalian cells expressing the mGluR subtypes: human mGluR1a, mGluR4a, mGluR5d or mGluR8b. The signal transduction coupling properties of mGluR4a and mGluR8b were switched from the adenylate cyclase (G(i)) pathway to the phospholipase C (G(q)) pathway by coexpression of a promiscuous G protein. Fluorometric imaging plate reader was used to measure changes in cytoplasmic calcium concentrations in response to agonist. Extracellular acidification from pH 8.0 to pH 6.5 progressively diminished mGluR4 responsiveness to the agonists L-glutamate and (2S,1'S,2'R)-2-(carboxycyclopropyl)glycine (L-CCG-I), and this inhibition was characterized by insurmountable antagonism. By comparison, extracellular acidification did not significantly alter mGluR8 responses to agonists. Furthermore, agonist activation of mGluR1a and mGluR5d was virtually unaffected by changes in pH. Because mGluR4 is expressed presynaptically and its activation inhibits the release of neurotransmitters such as glutamate and GABA, we propose that the net effect of proton inhibition of mGluR4 would be to reverse or prevent that suppression of neurotransmitter release. As such, local decreases in pH could have significant effects on the regulation of transmitter release and synaptic tone via modulation of mGluR4.
Assuntos
Concentração de Íons de Hidrogênio/efeitos dos fármacos , Prótons , Receptores de Glutamato Metabotrópico/metabolismo , Adenilil Ciclases/metabolismo , Regulação Alostérica/efeitos dos fármacos , Aminoácidos Dicarboxílicos/agonistas , Animais , Cálcio/agonistas , Cálcio/metabolismo , Cálcio/farmacologia , Linhagem Celular , Células Cultivadas , Líquido Extracelular/metabolismo , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Humanos , Líquido Intracelular/metabolismo , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fosfolipases Tipo C/metabolismo , Xenopus , Ácido gama-Aminobutírico/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of non-competitive mGlu5 receptor antagonists.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
Fenobam (1) was developed by McNeil Laboratories as an anxiolytic agent with an unknown molecular target in the late 1970s. In a recent publication, it was revealed that fenobam is a non-competitive mGluR5 antagonist. Herein, we present the structure-activity relationship of fenobam and its analogues and similarities between the SAR of mGluR5 antagonism and the SAR of CNS properties originally reported by McNeil are discussed.
Assuntos
Creatinina/química , Creatinina/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Ureia/química , Amidas/química , Cloretos/química , Imidazóis/síntese química , Concentração Inibidora 50 , Estrutura Molecular , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity.
Assuntos
Pirimidinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tionucleosídeos/farmacologia , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Fígado/efeitos dos fármacos , Microssomos/efeitos dos fármacos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Receptor de Glutamato Metabotrópico 5 , Estereoisomerismo , Relação Estrutura-Atividade , Tionucleosídeos/síntese química , Tionucleosídeos/químicaRESUMO
Studies of structure-activity relationships for the linker in a new series of metabotropic glutamate receptor 5 antagonists are presented together with in vitro and in vivo pharmacokinetic data.
Assuntos
Alcinos/química , Alcinos/farmacologia , Reagentes de Ligações Cruzadas/química , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Alcinos/síntese química , Alcinos/farmacocinética , Animais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
Synthesis and some structure-activity relationships for a new series of propargyl ethers as mGluR5 antagonists are reported.