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We have identified two chemical series of compounds acting as selective positive allosteric modulators (enhancers) of native and recombinant metabotropic glutamate 1 (mGlu1) receptors. These compounds did not directly activate mGlu1 receptors but markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy. Binding of these(More)
GABA(A) (γ-aminobutyric acid, type A) receptors are a family of ligand-gated ion channels that are essential for the regulation of central nervous system function. Benzodiazepines - which non-selectively target GABA(A) receptors containing the α1, α2, α3 or α5 subunits - have been in clinical use for decades and are still among the most widely prescribed(More)
BACKGROUND AND PURPOSE As baclofen is active in patients with anxiety disorders, GABAB receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABAB receptors have been studied to provide an alternative therapeutic avenue for modulation of GABAB receptors. The aim of this study was to(More)
We characterized modulation of the gamma-aminobutyric acid (GABA)-evoked responses of the diazepam-insensitive alpha 4 beta 2 gamma2 and alpha 6 beta 2 gamma 2 recombinant GABAA receptors. The partial agonist bretazenil potentiated the responses of both receptors with similar dose dependence but with a higher maximal enhancement at the alpha 4 beta 2 gamma(More)
A model of the rmGlu1 seven-transmembrane domain complexed with a negative allosteric modulator, 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)- 1,6-dihydro-pyrimidine-5-carbonitrile (EM-TBPC) was constructed. Although the mGlu receptors belong to the family 3 G-protein-coupled receptors with a low primary sequence similarity to(More)
1. The effects of the group II metabotropic glutamate receptor (mGluR) agonists DCG-IV and LY354740 were examined in neurones freshly dissociated from the rat cerebellum and olfactory bulb, using the whole-cell configuration of the patch-clamp technique. 2. Under experimental conditions in which K+ currents would be inward, rapid application of DCG-IV and(More)
GABAA α5 subunit-containing receptors are primarily expressed in the hippocampus and their role in learning and memory has been demonstrated recently by both genetic and pharmacological approaches. The objective of the study is to evaluate the cognitive effects of a novel GABAA α5 receptor inverse agonist, RO4938581 in rats and monkeys. The in vitro profile(More)
Vigilance, anxiety, memory, epileptogenic activity and muscle tension can be regulated by a modulation of GABAA-receptor function. A multitude of different GABAA-receptors exist in the brain due to the combinatorial assembly of various subunits encoded by at least 15 genes. The clarification of the physiological and pharmacological significance of(More)
Metabotropic glutamate (mGlu) receptors are a family of G-protein-coupled receptors that play central roles as modulators of both glutamatergic and other major neurotransmitter systems in CNS. Using molecular modeling, site-directed mutagenesis, [(3)H]LY354740 binding, [(35)S]GTPgammaS binding, and activation of GIRK current, we have been able to identify(More)
We have examined the pharmacological properties of native metabotropic glutamate (mGlu) receptors in freshly isolated rat cerebellar Golgi cells using the whole-cell configuration of the patch-clamp technique. Group II mGlu receptor agonists inhibited voltage-gated Ca(2+) channels (VGCC) currents in a reversible and concentration-dependent manner with a(More)