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See detailDesign and synthesis of PET-probes targeting AMPA-subtype receptors
Deverdenne, François ULg; Claes, Giselle ULg; Goffin, Eric ULg et al

Poster (2015, June 05)

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the ... [more ▼]

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data collected in recent years, the use of AMPA potentiators seems to be an interesting approach in the treatment of cognitive deficits (e.g. Alzheimer disease), schizophrenia or depression. Such AMPA signal potentiation could be mediated by positive allosteric modulators (PAMs) of the AMPA receptors, a class of compounds able to produce a fine signal tuning in the presence of the endogenous ligand in the synapse, providing less toxicity than direct agonists. With this approach, the laboratory of Medicinal Chemistry of Liège university developed many series of AMPA potentiators , among which 1,2,4-benzothiadiazine 1,1-dioxides (BTDs). In order to better understand the in vivo mapping of AMPA receptors and its evolution in neurological diseases, the present work aims at developing the design and the synthesis of BTDs positive allosteric modulators radiolabeled with a fluorine-18 atom. Based on previously synthesized series in this field, we investigate the synthesis of a new class of high-affinity AMPA potentiators characterized by the presence of a fluorine atom at selected positions on the structure of the AMPA potentiators. Thanks to in vitro pharmacological evaluations, we will further determine the best candidates for their fluorine-18 radiolabeling. [less ▲]

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See detailDesign, synthesis and pharmacological evaluation of dimeric ligands for the benzothiadiazine dioxide allosteric binding site of the AMPA receptors
Drapier, Thomas ULg; Francotte, Pierre ULg; Pirotte, Bernard ULg et al

Conference (2015, June 04)

L-glutamic acid is the major excitatory neurotransmitter in the brain. It exerts its effects through metabotropic and ionotropic receptors. Among the latter, three subtypes have been identified: NMDA ... [more ▼]

L-glutamic acid is the major excitatory neurotransmitter in the brain. It exerts its effects through metabotropic and ionotropic receptors. Among the latter, three subtypes have been identified: NMDA, AMPA and KA receptors. It is now well established that a deficit in glutamatergic signaling may be responsible for neurological disorders such as schizophrenia, depression, mild cognitive impairment and ADHD. Enhancement of the signal through positive allosteric modulators of AMPA receptors might be a therapeutic issue for these diseases. These compounds are expected to exert a fine tuning of the signal. Since they require the presence of the endogenous ligand to be active, they are expected to induce less toxicity than agonists. In this context, based on the structure of known allosteric modulators of AMPA receptors such as cyclothiazide (1) and IDRA 21 (2), the Laboratory of Medicinal Chemistry (University of Liège) has developed a series of 1,2,4-benzothiadiazine 1,1-dioxides with high potency as AMPA receptor potentiators, among which compounds (3) and (4). Crystallographic data obtained by the Department of Medicinal Chemistry (University of Copenhagen) highlighted that (3) and (4) bind to two contiguous sites at the dimer interface of the ligand binding domain of the AMPA receptor1,2. From these data, we may expect that the synthesis of dimeric molecules could lead to further improvement in affinity and activity. Our work consists in the development of a family of dimeric benzothiadiazine dioxides and their evaluation in a pharmacological assay. Several structural parameters such as the position of the bridge on the aromatic ring between the two heterocycles as well as its nature and length will be studied in order to determine their impact on the activity and thus the affinity. [less ▲]

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See detailDesign and synthesis of PET-probes targeting AMPA subtype receptors
Deverdenne, François ULg; Claes, Giselle ULg; Goffin, Eric ULg et al

Poster (2015, May 13)

The AMPA subtype of glutamatergic receptors is the main actor in the fast excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the ... [more ▼]

The AMPA subtype of glutamatergic receptors is the main actor in the fast excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data, it also appears that glutamatergic systems are involved in several pathological diseases. For instance, a lack of glutamatergic neurotransmission is observed in cognitive disorders or schizophrenia and an excessive activity is observed in Parkinson or Huntington diseases. The in vivo study of glutamate receptors mapping and its evolution appears to be an essential step for a better understanding of its implications. However, according to the literature, design of such a probe remains difficult due to the lack of specificity of the probes. Taking into account the potential in vitro and in vivo activity and specificity of benzothiadizine dioxides (BTDs) acting as AMPA positive allosteric modulators, we are investing the development of new compounds of this class radiolabeled with a fluorine-18 atom. Hence, we are currently developing new series of BTDs characterized by the presence of a fluorine atom and a 7-phenoxy-substituent that are expected to be more active and more specific. Finally, pharmacological tests to evaluate the best candidates for the radiochemical synthesis and in vivo evaluations are currently in progress. [less ▲]

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See detailßarrestin coupling of the orphan GPCR GPR27
Dupuis, Nadine ULg; Gilissen, Julie ULg; Derj, Anouar ULg et al

Poster (2015, January 27)

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See detailIdentification, Design and Evaluation of Pharmacological tools for the orphan GPCR GPR22
Geubelle, Pierre ULg; Gilissen, Julie ULg; Dupuis, Nadine ULg et al

Poster (2015, January 27)

GPCRs are the largest family of membrane receptors and are characterized by 7 transmembrane domains. GPR22 is a GPCR that has no known endogenous ligand and is thus considered "orphan". Its presence ... [more ▼]

GPCRs are the largest family of membrane receptors and are characterized by 7 transmembrane domains. GPR22 is a GPCR that has no known endogenous ligand and is thus considered "orphan". Its presence situated at the heart and brain levels makes it a potential target for new therapeutic pathways. This study consist in the identification of a synthetic ligand of GPR22 receptor to use it as a pharmacological tool in the study of the signaling channels of GPR22 in order to understand its role and to validate it as a new therapeutic target. The initial hypothesis was that GPR22 is coupled to the Gαi protein. [less ▲]

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See detailThermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces
Nørholm, Ann-Beth; Francotte, Pierre ULg; Goffin, Eric ULg et al

in Journal of Chemical Information & Modeling (2014), 54(12), 3404-3416

Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer’s disease. In the present study, we describe the ... [more ▼]

Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer’s disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, we found the OSP method to be more effective for this setup. Furthermore, from the molecular dynamics simulations, we extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, we used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted methyl compounds and used these predictions to characterize the modulator binding pocket for this scaffold of positive allosteric modulators.10.1021/ci500559b [less ▲]

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See detailIdentification, Design and Evaluation of Pharmacological tools for the orphan GPCR GPR22
Geubelle, Pierre ULg; Gilissen, Julie ULg; Dupuis, Nadine ULg et al

Poster (2014, November 21)

GPCRs are the largest family of membrane receptors and are characterized by seven transmembrane domains. This family of receptors is currently the most successfully targeted protein for therapeutic ... [more ▼]

GPCRs are the largest family of membrane receptors and are characterized by seven transmembrane domains. This family of receptors is currently the most successfully targeted protein for therapeutic purposes. GPR22 is a GPCR that was discovered in 1997. It has no known endogenous ligand and is thus considered "orphan". Its presence situated at the heart and brain levels makes it a potential target for new therapeutic pathways. The only information about its signaling channel could be its coupling with G proteins. This study consist in the identification of a synthetic ligand of GPR22 receptor to use it as a pharmacological tool in the study of the signaling channels of GPR22 in order to understand its role and to validate it as a new therapeutic target. The initial hypothesis was that GPR22 is coupled to the Gαi protein. [less ▲]

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See detailPositive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides
Francotte, Pierre ULg; Nørholm, Ann-Beth; Deva, Taru et al

in Journal of Medicinal Chemistry (2014), 57(22), 9539-9553

Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ... [more ▼]

Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg. [less ▲]

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See detailSynthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold
Nørholm, Ann-Beth; Francotte, Pierre ULg; Olsen, Lars et al

in Journal of Medicinal Chemistry (2014), 56(21), 8736-8745

Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer’s disease. The modulators bind within the dimer interface of ... [more ▼]

Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer’s disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = −7.5 kcal/mol and −TΔS = −1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496. [less ▲]

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See detailAGE-RELATED MACULAR DEGENERATION (AMD): FROM METABOLOMICS APPROACH TO THE INHIBITION OF PDK AS A NEW THERAPEUTIC TARGET
Arslan, Deniz ULg; Pirotte, Bernard ULg; De Tullio, Pascal ULg et al

Poster (2014, September 09)

Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is ... [more ▼]

Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase inhibitors (PDK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD disease [less ▲]

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See detailNMR in the Pharmaceutical and Biomedical areas for identification and quantification of drugs and metabolomics applications
LAMBERT, Vincent ULg; Dufour, Gilles ULg; Chiap, Patrice ULg et al

Conference (2014, June 23)

Nuclear Magnetic Resonance (NMR) is probably, with mass spectrometry, the most powerful analytical tool for the structural determination of organic compounds. For a long time and due to technical ... [more ▼]

Nuclear Magnetic Resonance (NMR) is probably, with mass spectrometry, the most powerful analytical tool for the structural determination of organic compounds. For a long time and due to technical limitations, the main applications of NMR were focused on chemistry (organic, inorganic and medicinal chemistry) or biochemistry (i.e. proteins and proteins ligands analysis). Indeed, despite of very interesting potential in terms of structural information, reproducibility, specificity, quantification, NMR suffered of a lack of sensitivity and sometime of resolution in the case of complex mixture analysis in comparison with other technics. However, since several years, important technical improvements such as huge increase in sensitivity, hyphenation of NMR with LC system, automation and development of 2D and presaturation sequences have opened new putative applications for NMR, specifically in the pharmaceutical and biomedical areas. Then, beside the mass and chromatographic technics classically used for drug analysis, NMR represents an interesting and complementary tool for many applications. In this presentation, we will describe some NMR applications related to the pharma area. Starting from the identification of xenobiotic metabolites by coupling LC-SPE-NMR data with LC-MS/MS results, quantification of cyclodextrines in complex media, identification of illicit compounds, we will finish with our recent metabolomics NMR developments. [less ▲]

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See detailLIGAND-INDEPENDENT IDENTIFICATION OF ORPHAN GPCR ARRESTIN BINDING
Dupuis, Nadine ULg; Gilissen, Julie ULg; Derj, Anouar ULg et al

Poster (2014, June 05)

Detailed reference viewed: 35 (10 ULg)
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See detailDesign and synthesis of high-affinity ligands of AMPA receptors and study of their Fluorine-18 radiolabeling
Deverdenne, François ULg; Goffin, Eric ULg; Plenevaux, Alain ULg et al

Poster (2014, June 05)

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the ... [more ▼]

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data collected in recent years, the use of AMPA potentiators seems to be an interesting approach in the treatment of cognitive deficits (e.g. Alzheimer disease), schizophrenia or depression. Such AMPA signal potentiation could be mediated by positive allosteric modulators (PAMs) of the AMPA receptors, a class of compounds able to produce a fine signal tuning in the presence of the endogenous ligand in the synapse, providing less toxicity than direct agonists. With this approach, the laboratory of Medicinal Chemistry of Liège university developed many series of AMPA potentiators , among which 1,2,4-benzothiadiazine 1,1-dioxides (BTDs). In order to better understand the in vivo mapping of AMPA receptors and its evolution in neurological diseases, the present work aims at developing the design and the synthesis of BTDs positive allosteric modulators radiolabeled with a fluorine-18 atom. Based on previously synthesized series in this field, we investigate the synthesis of a new class of high-affinity AMPA potentiators characterized by the presence of a fluorine atom at selected positions on the structure of the AMPA potentiators. Thanks to in vitro pharmacological evaluations, we will further determine the best candidates for their fluorine-18 radiolabeling. [less ▲]

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See detailInhibition of PDH Kinase as a new therapeutic target for Age-related Macular Degeneration (AMD)
Arslan, Deniz ULg; Pirotte, Bernard ULg; De Tullio, Pascal ULg et al

Poster (2014, June)

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a ... [more ▼]

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a cell, an organism or a biological system. This approach gives rise to a growing number of applications in many areas, such as biomarkers discovery, clinical studies, drug efficacy and toxicity evaluation, diagnostic tools, quality control. One of the most interesting features of metabolomics is its capability to extract biochemical information reflecting biological events and then to be a powerful tool in the knowledge of the aetiology of some pathologies. Indeed, it is clear that every disease could alter more or less drastically the metabolic profile of the patients. Then a metabolomics approach could highlight the biochemical pathways affected and could allow the identification of new putative therapeutic strategies or targets that could be useful in a new drug discovery strategy. As proteomics, metabolomics approach represents a new and powerful tool for Medicinal Chemistry. Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate DesHydrogenase Kinase inhibitors (PDHK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD disease. [less ▲]

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See detailValidation analytique d'une méthode chromatographique destinée à rechercher et à identifier les opiacés naturels ou (semi) synthétiques
DUBOIS, Nathalie ULg; Counerotte, Stéphane ULg; Goffin, Eric ULg et al

in Annales de Biologie Clinique (2014), 72(2), 197-206

L’identification de la substance absorbée par un consommateur d’opiacés peut être problématique dans la mesure où il n’existe pas de biomarqueur spécifique pour toutes les molécules. Nous avons développé ... [more ▼]

L’identification de la substance absorbée par un consommateur d’opiacés peut être problématique dans la mesure où il n’existe pas de biomarqueur spécifique pour toutes les molécules. Nous avons développé une technique de chromatographie liquide ultra-haute pression couplée à un spectromètre de masse en tandem qui permet l’identification et le dosage de 25 opiacés dans le plasma. La préparation de l’échantillon consiste en une extraction en phase solide sur colonnes Oasis ® MCX (Waters). La méthode a été validée selon les critères préconisés par la FDA, complètement pour 21 substances et avec quelques réserves pour les 4 produits restants. Cette méthode a été appliquée à 80 patients traités au CHU de Liège pour lesquels la recherche d’opiacés était positive. L’identification du produit consommé a été effective dans 86 % des cas. [less ▲]

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