Synthesis, Structure−Activity Relationship, and Receptor Pharmacology of a New Series of Quinoline Derivatives Acting as Selective, Noncompetitive mGlu1 Antagonists

Mabire, Dominique; Coupa, Sophie; Adelinet, Christophe; Poncelet, Alain; Simonnet, Yvan; Venet, Marc; Wouters, Ria; Lesage, Anne; Beijsterveldt, Ludy van; Bischoff, François

doi:10.1021/jm049499o

Cited by 93 publications

(91 citation statements)

References 39 publications

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“…CFMTI was more than 2000-fold more selective toward mGluR1 than mGluR5, and CFMTI showed no antagonistic, agonistic, or positive allosteric modulator activities toward other mGluR subtypes at concentrations up to 10 M. In addition, CFMTI had no activities on iGluRs, other neurotransmitter receptors, ion channels, or transporters tested using binding or functional studies. These data indicate that CFMTI is a highly potent and selective allosteric mGluR1 antagonist with good oral bioavailability and is one of the best-in-class among existing mGluR1 antagonists, such as R214127, JNJ16259685, EMQMCM, and FTIDC in vitro (Mabire et al, 2005;Suzuki et al, 2007).…”

Section: F B Cmentioning

confidence: 84%

Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one

Satow

Suzuki²,

Maehara³

et al. 2009

J Pharmacol Exp Ther

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A newly discovered metabotropic glutamate receptor (mGluR) 1 allosteric antagonist, 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one (CFMTI), was tested both in vitro and in vivo for its pharmacological effects. CFMTI demonstrated potent and selective antagonistic activity on mGluR1 in vitro and in vivo after oral administration. CFMTI inhibited L-glutamate-induced intracellular Ca 2ϩ mobilization in Chinese hamster ovary cells expressing human and rat mGluR1a, with IC 50 values of 2.6 and 2.3 nM, respectively. The selectivity of CFMTI to mGluR1 over mGluR5 was Ͼ2000-fold, and CFMTI at 10 M showed no agonistic or antagonistic activities toward other mGluR subtypes and other receptors. It antagonized face-washing behavior in mice induced by (S)-3,5-dihidroxyphenylglycine at a dose range of 3 to 30 mg/kg, for which receptor occupancy was 73 to 94%. As with the classical neuroleptic haloperidol and an atypical antipsychotic, clozapine, orally administered CFMTI reduced methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition (PPI) at the same dose range as required to antagonize the face-washing behavior. CFMTI and clozapine improved ketamine-induced hyperlocomotion, PPI disruption and (5S,10R)-(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-induced social withdrawal without any cataleptogenic activities, whereas haloperidol only improved ketamineinduced hyperlocomotion. CFMTI, unlike clozapine, caused neither hypolocomotion nor motor incoordination at therapeutic doses. In c-fos expression studies, CFMTI and clozapine increased the number of fos-positive neurons in the nucleus accumbens and medial prefrontal cortex but not in the dorsolateral striatum. These results suggest that the antipsychotic activities of mGluR1 antagonists are more similar to those of atypical antipsychotics than those of typical antipsychotics.L-Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and acts on both ligand-gated ion channels (ionotropic glutamate receptors; iGluRs) and G protein-coupled metabotropic glutamate receptors (mGluRs). The mGluR family consists of eight recep-A.S. and G.S. contributed equally to this work. Article, publication date, and citation information can be found at

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Section: F B Cmentioning

confidence: 84%

Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one

Satow

Suzuki²,

Maehara³

et al. 2009

J Pharmacol Exp Ther

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“…Subsequently, several novel negative allosteric mGlu1 receptor modulators (Table 6) were described that in functional in vitro assays had high potencies with IC 50 values in the low nanomolar range: (3,4- (Lavreysen et al, 2004), 6-amino-N-cyclohexyl-N,3-dimethylthiazolo [3,2-a]benzimidazole-2-carboxamide hydrochloride (YM-298198) (Kohara et al, 2005) (Kohara et al, 2007), FTIDC (Suzuki et al, 2007a), 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one (Fukuda et al, 2009) and compounds IX (Micheli et al, 2003) and X (Zheng et al, 2005) in Table 6. A number of additional negative allosteric mGlu1 receptor modulators (not shown in Table 6) have been described; their structures are given in the respective references (Mabire et al, 2005;Micheli et al, 2006;Di Fabio et al, 2007;Owen et al, 2007;Vanejevs et al, 2008;Sasikumar et al, 2009;Satoh et al, 2009). Some of these molecules showed good in vivo-activity, especially in models for chronic pain (see below).…”

Section: Allosteric Modulators Of the Mglu1 Receptor A Negative Allomentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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“…Based on this understanding, targeting activation or inhibition of specific mGlu receptor subtypes may provide a therapeutic benefit for a range of psychiatric and neurologic disorders. For neuropathic pain, inhibition of mGlu 1 is being pursued as a therapeutic intervention with success reported in preclinical models (Mabire et al, 2005;Bennett et al, 2012). Agonists of group II receptors have reached clinical trials for schizophrenia and anxiety with varying success (Schoepp et al, 2003;Patil et al, 2007;Dunayevich et al, 2008;Kinon et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Gregory

Conn

2015

Mol Pharmacol

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The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein-coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre-and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation.

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Synthesis, Structure−Activity Relationship, and Receptor Pharmacology of a New Series of Quinoline Derivatives Acting as Selective, Noncompetitive mGlu1 Antagonists

Cited by 93 publications

References 39 publications

Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one

Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

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