// UMR8601 - LCBPT - Pharmacochimie des récepteurs et des transporteurs des α-aminoacides
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UMR8601 - LCBPT
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Pharmacochimie des récepteurs et des transporteurs des α-aminoacides

Acher group web site

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Group members

Francine Acher (DR1 CNRS)

Isabelle McCort (CR1 CNRS)

Nicolas Pietrancosta (CR1 CNRS)

Delphine Rigault (Technician Univ Paris Descartes)

Berin Karaman (postdoc)

Blaise Dumat (ATER)

Mahamadou Djibo (PHD student)

Claudia Desole (PHD student)

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Research Interests

. The Acher group is focused on small molecules that target receptors and transporters of the CNS. Using synthetic organic chemistry and molecular modeling, we develop pharmacological and therapeutic tools. The team is involved in various projects from the initial design (molecules, 3D models...) all along to the in vivo studies. The interdisciplinary projects are made possible through numerous collaborations in the fields of pharmacology, molecular biology, cellular biology and behavior. Thus molecules that are developed in the group allow investigations of animal models of Parkinson’s disease motor symptoms, psychiatric diseases, cognition, pain and addiction as well as imaging and activation or transport mechanism elucidation.

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Research Topics

. Our research spans over two major fields that are actually linked in the synaptic event. .

1- Class C G Protein Coupled Receptors (GPCRs)

. GPCRs make up the largest family of small molecule targets on the drug market. However these mostly belong to class A, although class C receptors are perceived as highly valuable new targets. Among these metabotropic glutamate receptors (mGluRs) are found. Glutamate is the major excitatory neurotransmitter in the brain. It activates ligand gated ion channels (ionotropic receptors, iGluRs) and mGluRs. The iGluRs are responsible of the fast synaptic transmission while mGluRs are modulators of that event. Accordingly mGluRs may allow a fine tuning that is required for CNS treatments. Class C GPCRs are characterized by a large amino terminal domain that folds in two lobes connected by a flexible hinge and named Venus Flytrap (VFT) domain. The agonist binding site is located in the cleft near the hinge. It has been demonstrated that the VFT domain needs to adopt a closed conformation that induces a movement of the receptor dimer in order to trigger activation and signal transduction.

(JPG)

. Eight subtypes of mGluRs have been identified and classified in three groups (mGlu1-5 in group-I, mGlu2-3 in group-II and mGlu4-6-7-8 in group-III). Besides mGlu6 that is only present in the retina, group-III receptors are mostly presynaptic. Their activation will reduce the release of glutamate or GABA from hetero-receptors. We have been involved for many years in the development of group-III receptor orthosteric ligands and in activation mechanism investigation. We initially built a homology model of the VFT domain of mGlu4 docked L-AP4, a phosphonate analogue of glutamate that selectively activates group-III mGlu receptors. We then ran a virtual high through screening (vHTS) of the binding domain and discovered PCEP that was optimized in a series of analogues. PCEP allowed us to disclose a new binding pocket next to the glutamate binding site where in fact a chloride is bound. This new pocket is lined with selective residues which explains the mGlu4 selectivity of LSP4-2022 and will allow the design of other subtype selective orthosteric agonists. .

(JPG)

. We are currently pursuing the development of group-III selective ligands with the help of 3D-models. These compounds are tested in several in vivo models of neuropathologies such as pain, addiction and psychiatric diseases. Some of our group-III mGluR agonists (ACPT-I, LSP1-2111, LSP4-2022) have been evaluated in preclinical studies and show advantageous properties such as high aqueous solubility, brain penetration and metabolic stability. .

2- Vesicular transporters

. The second major topic of the group is focused on transporters. Presynaptic neurotransmitter vesicles play a key role in the neurotransmitter cycle by stocking and releasing it upon action potential. Vesicular neurotransmitter transporters (VNTs) allow the loading of these vesicles and are thus major actors of the neurotransmission. Initially the project aimed at providing new pharmacological tools, markers and mechanistic insights of the vesicular glutamate transporters (VGLUT). It was then extended to two other members of the same sub-family SLC17, sialin the sialic acid transporter which potentially transports Glu and Asp (Miyaji, 2008) and VNUT the nucleotide transporter characterized in 2008. (Sawada, 2008). .

Vesicular Glutamate Transporter (VGLUT)

. . The VGLUTs have only been rather recently identified and characterized. Since the uptake assay is tricky the pharmacology of these transporters remains limited to a few compounds. Rose Bengal (RB IC50 20nM), Trypan Blue (TB IC50 50 nM), quinolines (IC50 40-200µM) and glutamate analogues (IC50 200µM- 5mM) make up the list of VGLUT inhibitors. We have initially synthesized Rose Bengal analogues then moved to Trypan Blue ones. Synthesis and pharmacological evaluation of dye analogues are still ongoing. .

(JPG)

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Sialic acid transporter (Sialin)

. Several sialic acid analogues have been synthesized and tested. We chose the virtual high throughput screening (vHTS) approach to discover new inhibitors of sialin. A homology model was built, validated and docked with per-O-Ac 9-iodo-Neu5Ac a competitive inhibitor. A vHTS provided several hits among which, one was published (FR139317), others are being further evaluated. .

(JPG)

. Key words : selective orthosteric ligands, transporter inhibitors, probe synthesis, structure-activity relationship, small molecule-protein interaction, structure function studies, docking, virtual high throughput screening, hit optimization.

 

Past and present collaborations

Dr J.-P. PIN Institut de Génomique Fonctionelle, Département de Pharmacologie Moléculaire, Montpellier
Dr M. AMALRIC, Laboratoire de neurobiologie de la cognition, Marseille
Dr H.-O. BERTRAND Biovia/Dassault Systems, Orsay, France
Prof. J. NGAI, Functional Genomics Laboratory, Department of Molecular and Cell Biology, UC Berkeley, CA USA
Prof. A. PILC, Institute of Pharmacology, Krakow, Poland
Prof. N. NICOLETTI, Physiology and Pharmacology, Univerity of Rome, Italy
Dr P. PAOLETTI, Laboratoire de (...)

 

Publications

Tassin V., Girard B., Chotte A., Fontanaud P., Rigault D., Kalinichev M., Perroy J., Acher F, Fagni L. and Bertaso F. Frontiers in neural circuits 2016, 31, article number 31.
Wozniak M., Wieronska J. M., Acher F., Marciniak M., Lason-Tyburkiewicz M., Gruca P., Papp M. and Pilc A. The Involvement of GABAB signaling in the Antipsychotic-like Action of the Novel Orthosteric Agonist of mGlu4 Receptor, LSP4-2022. Cur Neuropharmacol 2016, 14(5), 413-426
Tora A. S., Rovira X., Dione I., (...)

 

 

 

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