RESUMEN
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.
Asunto(s)
Concentración de Iones de Hidrógeno/efectos de los fármacos , Protones , Receptores de Glutamato Metabotrópico/metabolismo , Adenilil Ciclasas/metabolismo , Regulación Alostérica/efectos de los fármacos , Aminoácidos Dicarboxílicos/agonistas , Animales , Calcio/agonistas , Calcio/metabolismo , Calcio/farmacología , Línea Celular , Células Cultivadas , Líquido Extracelular/metabolismo , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Humanos , Líquido Intracelular/metabolismo , Neurotransmisores/metabolismo , Neurotransmisores/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Fosfolipasas de Tipo C/metabolismo , Xenopus , Ácido gamma-Aminobutírico/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
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.
Asunto(s)
Alquinos/química , Alquinos/farmacología , Reactivos de Enlaces Cruzados/química , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Alquinos/síntesis química , Alquinos/farmacocinética , Animales , Hígado/efectos de los fármacos , Hígado/metabolismo , Estructura Molecular , Ratas , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
Synthesis and some structure-activity relationships for a new series of propargyl ethers as mGluR5 antagonists are reported.
Asunto(s)
Alquinos/química , Alquinos/farmacología , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Alquinos/síntesis química , Concentración 50 Inhibidora , Estructura Molecular , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Pirimidinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tionucleósidos/farmacología , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Hígado/efectos de los fármacos , Microsomas/efectos de los fármacos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Receptor del Glutamato Metabotropico 5 , Estereoisomerismo , Relación Estructura-Actividad , Tionucleósidos/síntesis química , Tionucleósidos/químicaRESUMEN
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.
Asunto(s)
Creatinina/química , Creatinina/farmacología , Imidazoles/química , Imidazoles/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Urea/química , Amidas/química , Cloruros/química , Imidazoles/síntesis química , Concentración 50 Inhibidora , Estructura Molecular , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
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.