Predicting Compound Selectivity by Self-Organizing Maps: Cross-Activities of Metabotropic Glutamate Receptor Antagonists

ChemMedChem ◽  
2006 ◽  
Vol 1 (10) ◽  
pp. 1066-1068 ◽  
Author(s):  
Tobias Noeske ◽  
Britta C. Sasse ◽  
Holger Stark ◽  
Christopher G. Parsons ◽  
Tanja Weil ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Antagonists ◽  
Self Organizing Maps ◽  
Metabotropic Glutamate ◽  
Glutamate Receptor Antagonists ◽  
Self Organizing

Synthesis of heterocyclic enol ethers and their use as group 2 metabotropic glutamate receptor antagonists

1999 ◽  
Vol 9 (15) ◽  
pp. 2173-2176 ◽  
Author(s):  
Sabine Kolczewski ◽  
Geo Adam ◽  
Heinz Stadler ◽  
Vincent Mutel ◽  
Jürgen Wichmann ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Antagonists ◽  
Enol Ethers ◽  
Metabotropic Glutamate ◽  
Glutamate Receptor Antagonists ◽  
Group 2

Differential Effects of Metabotropic Glutamate Receptor Antagonists on Bursting Activity in the Amygdala

1999 ◽  
Vol 81 (5) ◽  
pp. 2056-2065 ◽  
Author(s):  
N. Bradley Keele ◽  
Volker Neugebauer ◽  
Patricia Shinnick-Gallagher
Keyword(s):  
Glutamate Receptor ◽  
Stimulus Intensity ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Antagonists ◽  
Differential Effects ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Glutamate Receptor Antagonists ◽  
Group Ii ◽  
Bursting Activity

Differential effects of metabotropic glutamate receptor antagonists on bursting activity in the amygdala. Metabotropic glutamate receptors (mGluRs) are implicated in both the activation and inhibition of epileptiform bursting activity in seizure models. We examined the role of mGluR agonists and antagonists on bursting in vitro with whole cell recordings from neurons in the basolateral amygdala (BLA) of amygdala-kindled rats. The broad-spectrum mGluR agonist 1 S,3 R-1-aminocyclopentane dicarboxylate (1 S,3 R-ACPD, 100 μM) and the group I mGluR agonist ( S)-3,5-dihydroxyphenylglycine (DHPG, 20 μM) evoked bursting in BLA neurons from amygdala-kindled rats but not in control neurons. Neither the group II agonist (2 S,3 S,4 S)-α-(carboxycyclopropyl)-glycine (l-CCG-I, 10 μM) nor the group III agonistl-2-amino-4-phosphonobutyrate (l-AP4, 100 μM) evoked bursting. The agonist-induced bursting was inhibited by the mGluR1 antagonists (+)-α-methyl-4-carboxyphenylglycine [(+)-MCPG, 500 μM] and ( S)-4-carboxy-3-hydroxyphenylglycine [( S)-4C3HPG, 300 μM]. Kindling enhanced synaptic strength from the lateral amygdala (LA) to the BLA, resulting in synaptically driven bursts at low stimulus intensity. Bursting was abolished by (S)-4C3HPG. Further increasing stimulus intensity in the presence of ( S)-4C3HPG (300 μM) evoked action potential firing similar to control neurons but did not induce epileptiform bursting. In kindled rats, the same threshold stimulation that evoked epileptiform bursting in the absence of drugs elicited excitatory postsynaptic potentials in ( S)-4C3HPG. In contrast (+)-MCPG had no effect on afferent-evoked bursting in kindled neurons. Because (+)-MCPG is a mGluR2 antagonist, whereas ( S)-4C3HPG is a mGluR2 agonist, the different effects of these compounds suggest that mGluR2 activation decreases excitability. Together these data suggest that group I mGluRs may facilitate and group II mGluRs may attenuate epileptiform bursting observed in kindled rats. The mixed agonist–antagonist ( S)-4C3HPG restored synaptic transmission to control levels at the LA-BLA synapse in kindled animals. The different actions of ( S)-4C3HPG and (+)-MCPG on LA-evoked bursting suggests that the mGluR1 antagonist–mGluR2 agonist properties may be the distinctive pharmacology necessary for future anticonvulsant compounds.

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