Synthesis and Preliminary Biological Evaluation of 2′-Substituted 2-(3′-Carboxybicyclo[1.1.1]pentyl)glycine Derivatives as Group I Selective Metabotropic Glutamate Receptor Ligands

ChemMedChem ◽  
2006 ◽  
Vol 1 (3) ◽  
pp. 358-365 ◽  
Author(s):  
Roberto Pellicciari ◽  
Rosanna Filosa ◽  
Maria Carmela Fulco ◽  
Maura Marinozzi ◽  
Antonio Macchiarulo ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Biological Evaluation ◽  
Receptor Ligands ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Glycine Derivatives

scholarly journals In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands

2004 ◽  
Vol 88 (5) ◽  
pp. 1068-1077 ◽  
Author(s):  
Ilse Smolders ◽  
Hilde Lindekens ◽  
Ralph Clinckers ◽  
Alfred Meurs ◽  
Michael J. O'Neill ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Ligands ◽  
Limbic Seizures ◽  
Metabotropic Glutamate ◽  
Group I

Synthesis and biological evaluation of (−)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands

2014 ◽  
Vol 12 (47) ◽  
pp. 9638-9643 ◽  
Author(s):  
Chiara Zanato ◽  
Sonia Watson ◽  
Guy S. Bewick ◽  
William T. A. Harrison ◽  
Matteo Zanda
Keyword(s):  
Kainic Acid ◽  
Glutamate Receptor ◽  
Phospholipase D ◽  
Metabotropic Glutamate Receptor ◽  
Muscle Spindles ◽  
Biological Evaluation ◽  
Receptor Ligands ◽  
Mglu Receptor ◽  
Metabotropic Glutamate ◽  
Synthesis And Biological Evaluation

A “click” 4-(1,2,3-triazolyl)-kainate derivative and its biotinylated version potently increase stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor.

Metabotropic Glutamate Receptor Agonists Alter Neuronal Excitability and Ca2+ Levels via the Phospholipase C Transduction Pathway in Cultured Purkinje Neurons

1997 ◽  
Vol 78 (1) ◽  
pp. 63-75 ◽  
Author(s):  
Jeffrey G. Netzeband ◽  
Kathy L. Parsons ◽  
Dan D. Sweeney ◽  
Donna L. Gruol
Keyword(s):  
Phospholipase C ◽  
Glutamate Receptor ◽  
Neuronal Excitability ◽  
Metabotropic Glutamate Receptor ◽  
Purkinje Neurons ◽  
Transduction Pathway ◽  
Electrophysiological Response ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Intracellular Ca

Netzeband, Jeffrey G., Kathy L. Parsons, Dan D. Sweeney, and Donna L. Gruol. Metabotropic glutamate receptor agonists alter neuronal excitability and Ca2+ levels via the phospholipase C transduction pathway in cultured Purkinje neurons. J. Neurophysiol. 78: 63–75, 1997. Selective agonists for metabotropic glutamate receptor (mGluR) subtypes were tested on mature, cultured rat cerebellar Purkinje neurons (≥21 days in vitro) to identify functionally relevant mGluRs expressed by these neurons and to investigate the transduction pathways associated with mGluR-mediated changes in membrane excitability. Current-clamp recordings (nystatin/perforated-patch method) were used to measure the membrane response of Purkinje neurons to brief microperfusion pulses (1.5 s) of the group I (mGluR1/mGluR5) agonists (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid (300 μM), quisqualate (5 μM), and ( R,S)-3,5-dihydroxyphenylglycine (50–500 μM). All group I mGluR agonists elicited biphasic membrane responses and burst activity in the Purkinje neurons. In addition, the group I mGluR agonists produced alterations in the active membrane properties of the Purkinje neurons and depressed the off response after hyperpolarizing current injection. In parallel microscopic Ca2+ imaging experiments, application of the group I mGluR agonists to fura-2-loaded cells elicited increases in intracellular Ca2+ in both the somatic and dendritic regions. The group II (mGluR2/mGluR3) agonist (2 S,3 S,4 S)-α-(carboxycyclopropyl)-glycine (10 μM) and the group III (mGluR4/mGluR6/mGluR7/mGluR8) agonists l(+)-2-amino-4-phosphonobutyric acid (1 mM) and O-phospho-l-serine (200 μM) had no effect on the membrane potential or intracellular Ca2+ levels of the Purkinje neurons. The cultured Purkinje neurons, but not granule neurons or interneurons, showed immunostaining for mGluR1α in both the somatic and dendritic regions. All effects of the group I mGluR agonists were blocked by (+)-α-methyl-4-carboxyphenylglycine (1 mM), an mGluR antagonist. Furthermore, the phospholipase C inhibitor 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (2 μM) blocked the group I mGluR agonist-mediated electrophysiological response and greatly attenuated the Ca2+ signal elicited by group I mGluR agonists, particularly in the dendrites. The inactive analogue1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]2,5-pyrrolidine-dione (2 μM) was relatively ineffective against the electrophysiological response and Ca2+ signal. These results indicate that functional group I mGluRs (but not group II or III mGluRs) can be activated on mature Purkinje neurons in culture and result in changes in neuronal excitability and intracellular Ca2+ mediated through phospholipase C. These data obtained from a defined neuronal type, the Purkinje neuron, confirm biochemical and molecular studies on the transduction mechanisms of group I mGluRs and show that this transduction pathway is linked to neuronal excitability and intracellular Ca2+ release in the Purkinje neurons.

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