References of "Hanson, Julien"
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See detailGPCRs in immunity: atypical receptors and novel concepts
Hanson, Julien ULg; Chevigné, Andy

in Biochemical Pharmacology (in press)

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See detailHuman herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7
Szpakowska, Martyna; Dupuis, Nadine ULg; Baragli, Alessandra et al

in Biochemical Pharmacology (in press)

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See detailDESIGN OF HIGH-AFFINITY LIGANDS FOR THE BENZOTHIADIAZINE ALLOSTERIC BINDING SITE OF THE AMPA RECEPTORS
Drapier, Thomas ULg; Geubelle, Pierre ULg; Bouckaert, Charlotte et al

Poster (2016, May 26)

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 mild cognitive impairment, schizophrenia, depression, 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 and IDRA 21, 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. Crystallographic data obtained by the Department of Drug Design and Pharmacology (University of Copenhagen) highlighted those potentiators bind to two contiguous sites at the dimer interface of the ligand binding domain (LBD) of the AMPA receptor1,2. Based on these data, we may expect that the synthesis of dimeric molecules could lead to further improvement in affinity and activity. This assumption was reinforced by docking experiments conducted with virtual examples of dimeric compounds on the GluA2-LBD (collaboration with NAMEDIC). The present work is thus focusing on the preparation of a family of dimeric benzothiadiazine dioxides. Moreover, in collaboration with GIGA-Molecular Pharmacology, we are developing a pharmacological in vitro assay based on the measurement of Ca2+ inflow through a fluorimetric method. This medium-throughput screening will enable the characterization of our new compounds and the validation of our working hypothesis. [less ▲]

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See detailA forskolin free method for measuring cAMP modulation by Gi coupled receptors
Hanson, Julien ULg

Conference (2016, April 18)

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See detailIdentification of small molecule ligands for the orphan GPCR GPR27
Dupuis, Nadine ULg; Gilissen, Julie; Derj, Anouar ULg et al

Poster (2016, January 25)

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See detailTargeted and random mutagenesis of orphan GPCRs of the SREB family
Laschet, Céline ULg; Dupuis, Nadine ULg; Derj, Anouar ULg et al

Poster (2016, January 25)

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See detailInsight into SUCNR1 (GPR91) structure and function
Gilissen, Julie ULg; Jouret, François ULg; Pirotte, Bernard ULg et al

in Pharmacology & Therapeutics (2016)

SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs ... [more ▼]

SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate. According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy. The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor,more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed. [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 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 detailForskolin-free cAMP assay for Gi-coupled receptors
Gilissen, Julie ULg; Geubelle, Pierre ULg; Dupuis, Nadine ULg et al

in Biochemical Pharmacology (2015)

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See detailIdentification of modulators for SUCNR1 by screening of a SOSA library with a bioluminescent cAMP assay
Gilissen, Julie; Dupuis, Nadine ULg; Derj, Anouar et al

Conference (2014, November 21)

Background Succinic acid (SA), a metabolic component that takes part in the citric acid cycle, has been described as the cognate agonist for the orphan receptor SUCNR1 (GPR91). This receptor belongs to ... [more ▼]

Background Succinic acid (SA), a metabolic component that takes part in the citric acid cycle, has been described as the cognate agonist for the orphan receptor SUCNR1 (GPR91). This receptor belongs to the G Protein-Coupled Receptor family (GPCR), that play an essential role in regulating many physiological functions and represent 30% of targets for currently marketed drugs. Several studies on KO models suggested different roles for SUCNR1 through its inactivation. Nevertheless, the characterization of the pharmacology and physiology of SUCNR1 is limited by the lack of small molecules used as pharmacological tools. Methods In order to identify ligands modulating SUCNR1 Gαi activity, we adapted a specific cAMP assay based on a modified luciferase fused with cAMP binding domain (Glosensor® promega corporation). Upon cAMP binding, conformational changes induce luminescent signal. This sensitive assay was carried out in a real time measurements fashion. It was compatible with the screening of chemical libraries. We utilized a SOSA library based on the principle that active compounds might have an activity on new targets at high concentration. Results We performed a primary agonist screening on 1280 compounds of a SOSA library at two different concentrations (100 and 10µM) with a cAMP assay (Z’=0,4-0,6). We selected 114 out of them that were characterized at least by an increase (or decrease) of 20% of the luminescent signal from HEK293.SUCNR1 cells. These compounds were subjected to a secondary screening performed in triplicates. Results analysis provided 16 putative modulators of SUCNR1 Gαi activity. We followed a similar strategy in another screening to find candidates with an antagonist profile. In parallel, we docked a part of the ZINC database ‘‘lead-like’’ molecules against SUCNR1 protein built by homology modelling from the β2-adrenergic receptor. This virtual screening has sorted 30 compounds with substantial theoretical affinity. They are currently undergoing functional evaluation in the cAMP assay. Conclusions We set up a real-time luminometric cAMP assay for SUCNR1. We selected a dozen of putative modulators of SUCNR1 that were selected for thorough evaluation. Furthermore, we obtained 30 potentially active compounds from a virtual screening that are assayed for functional activity at the receptor. The pharmacology of hits is currently characterized with different models and assays. [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 detailLigand-independent Identification of orphan GPCR Signaling pathways
Dupuis, Nadine ULg; Gilissen, Julie; Derj, Anouar ULg et al

Conference (2014, July 16)

Detailed reference viewed: 30 (3 ULg)
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: 40 (11 ULg)