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ABSTRACT: 1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency.
Bioorganic & medicinal chemistry letters 08/2012; 22(20):6454-9. · 2.65 Impact Factor
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Bazoumana Ouattara,
Laurent Grégoire,
Marc Morissette,
Fabrizio Gasparini, Ivo Vranesic,
Graeme Bilbe,
Donald R Johns,
Alex Rajput,
Oleh Hornykiewicz,
Ali H Rajput,
Baltazar Gomez-Mancilla,
Thérèse Di Paolo
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ABSTRACT: Metabotropic glutamate receptors type 5 (mGluR5) are implicated in regulation of synaptic plasticity and learning, and were the focus of our investigation in human Parkinson's disease (PD) patients with dyskinesias and wearing-off, and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with dyskinesias. Using the selective mGluR5 ligand [(3)H]ABP688 autoradiography, we measured mGluR5 in brain slices from 11 normal and 14 PD patients and from MPTP monkeys, in relation to motor complications (dyskinesias and wearing-off) associated with treatment with l-dopa. In 16 monkeys with a bilateral MPTP lesion and four controls, [(3)H]ABP688 specific binding was elevated in the striatum of dyskinetic l-dopa-treated MPTP monkeys but not in MPTP monkeys without dyskinesias compared to controls. PD patients with motor complications (either dyskinesias or wearing-off) had higher [(3)H]ABP688 specific binding compared to those without motor complications and controls in putamen, external and internal globus pallidus. Elevated glutamatergic transmission as measured with increased mGluR5 specific binding was associated with motor complications and its antagonism could be targeted for their treatment.
Neurobiology of aging 07/2011; 32(7):1286-95. · 5.94 Impact Factor
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ABSTRACT: Overactivity of glutamatergic transmission has been implicated in Parkinson's disease (PD) and levodopa (L-Dopa)-induced dyskinesias. Striatal metabotropic glutamate receptors type 5 (mGluR5) are abundant and provide specific targets to modulate glutamatergic activity. This study investigated the acute effects of the novel mGluR5 antagonist AFQ056 on motor behavior in L-Dopa-treated monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion to model PD. Six Macaca fascicularis MPTP monkeys were treated repeatedly with L-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores, but also induced dyskinesias. When AFQ056 (doses of 5, 25, 125 or 250mg/kg) was administered one hour prior to a high dose of L-Dopa, the antiparkinsonian activity of L-Dopa was maintained as measured with locomotion and antiparkinsonian scores, whereas dyskinesias were significantly reduced at 25, 125 and 250mg/kg AFQ056 for peak dyskinesia score and at 125 and 250mg/kg for the 1h peak period of dyskinesia score. Administration of AFQ056 one hour before L-Dopa led to peak or elevated plasma AFQ056 concentrations occurring close to L-Dopa peak-dose dyskinesias. We next investigated AFQ056 25mg/kg combined with a low dose of L-Dopa. The antiparkinsonian activity of L-Dopa was increased as measured with locomotion, while dyskinesias remained low at these doses. Our results show a beneficial motor effect of AFQ056 with L-Dopa in MPTP monkeys. This supports the therapeutic use of an mGluR5 antagonist to restore normal glutamatergic neurotransmission in PD and decrease dyskinesias.
Parkinsonism & Related Disorders 02/2011; 17(4):270-6. · 3.80 Impact Factor
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ABSTRACT: High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.
Bioorganic & medicinal chemistry letters 11/2009; 20(1):184-8. · 2.65 Impact Factor
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Samuel Hintermann, Ivo Vranesic,
Hans Allgeier,
Armin Brülisauer,
Daniel Hoyer,
Michel Lemaire,
Thomas Moenius,
Stephan Urwyler,
Steven Whitebread,
Fabrizio Gasparini,
Yves P Auberson
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ABSTRACT: [(11)C]ABP688 (2) has recently been demonstrated to be a useful PET tracer for in vivo imaging of the metabotropic glutamate receptors type 5 (mGluR5) in rodents. We describe here the identification and preclinical profiling of ABP688 and its tritiated version [(3)H]ABP688, and show that its high affinity (K(d)=2nM), selectivity, and pharmacokinetic properties fulfill all requirements for development as a PET tracer for clinical imaging of the mGlu5 receptor.
Bioorganic & Medicinal Chemistry 02/2007; 15(2):903-14. · 2.92 Impact Factor
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Fabrizio Gasparini,
Hendrik Andres,
Peter Josef Flor,
Micheline Heinrich,
Werner Inderbitzin,
Kurt Lingenhöhl,
Hanspeter Müller,
Veronica Cecilia Munk,
Kyla Omilusik,
Christine Stierlin,
Natacha Stoehr, Ivo Vranesic,
Rainer Kuhn
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ABSTRACT: The synthesis of a new potent, subtype-selective radioligand [(3)H]-M-MPEP (2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine) and its in vitro pharmacological characteristics are described. Science Ltd.
Bioorganic & Medicinal Chemistry Letters 03/2002; 12(3):407-9. · 2.55 Impact Factor
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Adriana Pagano,
Doris Rüegg,
Stephane Litschig,
Natacha Stoehr,
Christine Stierlin,
Micheline Heinrich,
Philipp Floersheim,
Laurent Prezèau,
Fiona Carroll,
Jean-Philippe Pin,
Antonio Cambria, Ivo Vranesic,
Peter Josef Flor,
Fabrizio Gasparini,
Rainer Kuhn
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ABSTRACT: We have investigated the mechanism of inhibition and site of action of the novel human metabotropic glutamate receptor 5 (hmGluR5)
antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), which is structurally unrelated to classical metabotropic glutamate
receptor (mGluR) ligands. Schild analysis indicated that MPEP acts in a non-competitive manner. MPEP also inhibited to a large
extent constitutive receptor activity in cells transiently overexpressing rat mGluR5, suggesting that MPEP acts as an inverse
agonist. To investigate the molecular determinants that govern selective ligand binding, a mutagenesis study was performed
using chimeras and single amino acid substitutions of hmGluR1 and hmGluR5. The mutants were tested for binding of the novel
mGluR5 radioligand [3H]2-methyl-6-(3-methoxyphenyl)ethynyl pyridine (M-MPEP), a close analog of MPEP. Replacement of Ala-810 in transmembrane (TM)
VII or Pro-655 and Ser-658 in TMIII with the homologous residues of hmGluR1 abolished radioligand binding. In contrast, the
reciprocal hmGluR1 mutant bearing these three residues of hmGluR5 showed high affinity for [3H]M-MPEP. Radioligand binding to these mutants was also inhibited by 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt), a structurally unrelated non-competitive mGluR1 antagonist previously shown to interact
with residues Thr-815 and Ala-818 in TMVII of hmGluR1. These results indicate that MPEP and CPCCOEt bind to overlapping binding
pockets in the TM region of group I mGluRs but interact with different non-conserved residues.
Journal of Biological Chemistry 10/2000; 275(43):33750-33758. · 4.77 Impact Factor
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Fabrizio Gasparini,
Philipp Floersheim,
Peter Josef Flor,
Micheline Heinrich,
Werner Inderbitzin,
David Ott,
Adriana Pagano,
Christine Stierlin,
Natacha Stoehr, Ivo Vranesic,
Rainer Kuhn
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ABSTRACT: We have investigated the mechanism of inhibition of the new group I mGluR antagonists CPCCOEt and MPEP and determined that both compounds have a non-competitive mode of inhibition. Furthermore using chimeric/mutated receptors constructs we have found that these antagonists act at a novel pharmacological site located in the trans-membrane (TM). Specific non-conserved amino acid residues in the TM domain have been identified which are necessary for the inhibition by CPCCOEt and MPEP of the mGlu1 and mGlu5 receptors, respectively. Using molecular modeling a model of the TM domain was built for both mGlu1 and mGlu5 receptor subtypes. Docking of CPCCOEt and MPEP into their respective model allowed the modelisation of the novel binding site.
Il Farmaco.
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Fabrizio Gasparini,
Kurt Lingenhöhl,
Natacha Stoehr,
Peter J Flor,
Micheline Heinrich, Ivo Vranesic,
Michel Biollaz,
Hans Allgeier,
Roland Heckendorn,
Stephan Urwyler,
Mark A Varney,
Edwin C Johnson,
Stephen D Hess,
Sara P Rao,
Aida I Sacaan,
Emily M Santori,
Gönul Veliçelebi,
Rainer Kuhn
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ABSTRACT: In the present paper we describe 2-methyl-6-(phenylethynyl)-pyridine (MPEP) as a potent, selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGlu5). At the human mGlu5a receptor expressed in recombinant cells, MPEP completely inhibited quisqualate-stimulated phosphoinositide (PI) hydrolysis with an IC50 value of 36 nM while having no agonist or antagonist activities at cells expressing the human mGlu1b receptor at concentrations up to 30 μM. When tested at group II and III receptors, MPEP did not show agonist or antagonist activity at 100 μM on human mGlu2, -3, -4a, -7b, and -8a receptors nor at 10 μM on the human mGlu6 receptor. Electrophysiological recordings in Xenopus laevis oocytes demonstrated no significant effect at 100 μM on human NMDA (NMDA1A/2A), rat AMPA (Glu3-(flop)) and human kainate (Glu6-(IYQ)) receptor subtypes nor at 10 μM on the human NMDA1A/2B receptor. In rat neonatal brain slices, MPEP inhibited DHPG-stimulated PI hydrolysis with a potency and selectivity similar to that observed on human mGlu receptors. Furthermore, in extracellular recordings in the CA1 area of the hippocampus in anesthetized rats, the microiontophoretic application of DHPG induced neuronal firing that was blocked when MPEP was administered by iontophoretic or intravenous routes. Excitations induced by microiontophoretic application of AMPA were not affected.
Neuropharmacology.
