48 results on '"Chaumont-Dubel, Séverine"'
Search Results
2. Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide
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Drop, Marcin, Jacquot, Florian, Canale, Vittorio, Chaumont-Dubel, Severine, Walczak, Maria, Satała, Grzegorz, Nosalska, Klaudia, Mahoro, Gilbert Umuhire, Słoczyńska, Karolina, Piska, Kamil, Lamoine, Sylvain, Pękala, Elżbieta, Masurier, Nicolas, Bojarski, Andrzej J., Pawłowski, Maciej, Martinez, Jean, Subra, Gilles, Bantreil, Xavier, Lamaty, Frédéric, Eschalier, Alain, Marin, Philippe, Courteix, Christine, and Zajdel, Paweł
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- 2021
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3. A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties
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Canale, Vittorio, Grychowska, Katarzyna, Kurczab, Rafał, Ryng, Mateusz, Keeri, Abdul Raheem, Satała, Grzegorz, Olejarz-Maciej, Agnieszka, Koczurkiewicz, Paulina, Drop, Marcin, Blicharz, Klaudia, Piska, Kamil, Pękala, Elżbieta, Janiszewska, Paulina, Krawczyk, Martyna, Walczak, Maria, Chaumont-Dubel, Severine, Bojarski, Andrzej J., Marin, Philippe, Popik, Piotr, and Zajdel, Paweł
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- 2020
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4. Superiority of the Triple-Acting 5-HT6R/5-HT3R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
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Grychowska, Katarzyna, primary, López-Sánchez, Uriel, additional, Vitalis, Mathieu, additional, Canet, Geoffrey, additional, Satała, Grzegorz, additional, Olejarz-Maciej, Agnieszka, additional, Gołębiowska, Joanna, additional, Kurczab, Rafał, additional, Pietruś, Wojciech, additional, Kubacka, Monika, additional, Moreau, Christophe, additional, Walczak, Maria, additional, Blicharz-Futera, Klaudia, additional, Bento, Ophélie, additional, Bantreil, Xavier, additional, Subra, Gilles, additional, Bojarski, Andrzej J., additional, Lamaty, Frédéric, additional, Becamel, Carine, additional, Zussy, Charleine, additional, Chaumont-Dubel, Séverine, additional, Popik, Piotr, additional, Nury, Hugues, additional, Marin, Philippe, additional, Givalois, Laurent, additional, and Zajdel, Paweł, additional
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- 2023
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5. Classification and signaling characteristics of 5-HT receptors: toward the concept of 5-HT receptosomes
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Marin, Philippe, primary, Bécamel, Carine, additional, Chaumont-Dubel, Séverine, additional, Vandermoere, Franck, additional, Bockaert, Joël, additional, and Claeysen, Sylvie, additional
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- 2020
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6. Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties
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Vanda, David, Soural, Miroslav, Canale, Vittorio, Chaumont-Dubel, Séverine, Satała, Grzegorz, Kos, Tomasz, Funk, Petr, Fülöpová, Veronika, Lemrová, Barbora, Koczurkiewicz, Paulina, Pękala, Elżbieta, Bojarski, Andrzej J., Popik, Piotr, Marin, Philippe, and Zajdel, Paweł
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- 2018
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7. A Serotonergic Axon-Cilium Synapse Drives Nuclear Signaling to Maintain Chromatin Accessibility
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Sheu, Shu-Hsien, primary, Upadhyayula, Srigokul, additional, Dupuy, Vincent, additional, Pang, Song, additional, Deng, Fei, additional, Wan, Jinxia, additional, Walpita, Deepika, additional, Pasolli, H Amalia, additional, Houser, Justin, additional, Sanchez-Martinez, Silvia, additional, Brauchi, Sebastian E, additional, Banala, Sambashiva, additional, Freeman, Melanie, additional, Xu, C Shan, additional, Kirchhausen, Tom, additional, Hess, Harald F, additional, Lavis, Luke, additional, Li, Yulong, additional, Chaumont-Dubel, Séverine, additional, and Clapham, David E, additional
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- 2023
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8. The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication
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Fumagalli, Amos, Heuninck, Joyce, Pizzoccaro, Anne, Moutin, Enora, Koenen, Joyce, Séveno, Martial, Durroux, Thierry, Junier, Marie-Pierre, Schlecht-Louf, Géraldine, Bachelerie, Francoise, Schütz, Dagmar, Stumm, Ralf, Smit, Martine J., Guérineau, Nathalie C., Chaumont-Dubel, Séverine, and Marin, Philippe
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- 2020
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9. Physical interaction between neurofibromin and serotonin 5-HT₆ receptor promotes receptor constitutive activity
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Nadim, Wissem Deraredj, Chaumont-Dubel, Séverine, Madouri, Fahima, Cobret, Laetitia, De Tauzia, Marie-Ludivine, Zajdel, Pawel, Bénédetti, Hélène, Marin, Philippe, and Morisset-Lopez, Séverine
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- 2016
10. Superiority of the Triple-Acting 5-HT6R/5-HT3R Antagonist and MAO-B Reversible Inhibitor PZ-1922over 5-HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
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Grychowska, Katarzyna, López-Sánchez, Uriel, Vitalis, Mathieu, Canet, Geoffrey, Satała, Grzegorz, Olejarz-Maciej, Agnieszka, Gołębiowska, Joanna, Kurczab, Rafał, Pietruś, Wojciech, Kubacka, Monika, Moreau, Christophe, Walczak, Maria, Blicharz-Futera, Klaudia, Bento, Ophélie, Bantreil, Xavier, Subra, Gilles, Bojarski, Andrzej J., Lamaty, Frédéric, Becamel, Carine, Zussy, Charleine, Chaumont-Dubel, Séverine, Popik, Piotr, Nury, Hugues, Marin, Philippe, Givalois, Laurent, and Zajdel, Paweł
- Abstract
The multifactorial origin and neurochemistry of Alzheimer’s disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT6R antagonism and interaction with 5-HT3R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT6R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922, but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD.
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- 2023
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11. Impact of 5-HT6 Receptor Subcellular Localization on Its Signaling and Its Pathophysiological Roles
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Chaumont-Dubel, Séverine, primary, Galant, Sonya, additional, Prieur, Matthieu, additional, Bouschet, Tristan, additional, Bockaert, Joël, additional, and Marin, Philippe, additional
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- 2023
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12. Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT6 and D3R Affinity in the 1H-Pyrrolo[3,2-c]quinoline Series
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Grychowska, Katarzyna, primary, Pietruś, Wojciech, additional, Kulawik, Ludmiła, additional, Bento, Ophélie, additional, Satała, Grzegorz, additional, Bantreil, Xavier, additional, Lamaty, Frédéric, additional, Bojarski, Andrzej J., additional, Gołębiowska, Joanna, additional, Nikiforuk, Agnieszka, additional, Marin, Philippe, additional, Chaumont-Dubel, Séverine, additional, Kurczab, Rafał, additional, and Zajdel, Paweł, additional
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- 2023
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13. Spatiotemporal dynamics of 5-HT6 receptor ciliary localization during mouse brain development
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Dupuy, Vincent, primary, Prieur, Matthieu, additional, Pizzoccaro, Anne, additional, Margarido, Clara, additional, Valjent, Emmanuel, additional, Bockaert, Joël, additional, Bouschet, Tristan, additional, Marin, Philippe, additional, and Chaumont-Dubel, Séverine, additional
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- 2023
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14. 1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity
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Canale, Vittorio, primary, Trybała, Wojciech, additional, Chaumont-Dubel, Séverine, additional, Koczurkiewicz-Adamczyk, Paulina, additional, Satała, Grzegorz, additional, Bento, Ophélie, additional, Blicharz-Futera, Klaudia, additional, Bantreil, Xavier, additional, Pękala, Elżbieta, additional, Bojarski, Andrzej J., additional, Lamaty, Frédéric, additional, Marin, Philippe, additional, and Zajdel, Paweł, additional
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- 2022
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15. Early5‐HT 6receptor blockade prevents symptom onset in a model of adolescent cannabis abuse
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Berthoux, Coralie, primary, Hamieh, Al Mahdy, additional, Rogliardo, Angelina, additional, Doucet, Emilie L, additional, Coudert, Camille, additional, Ango, Fabrice, additional, Grychowska, Katarzyna, additional, Chaumont‐Dubel, Séverine, additional, Zajdel, Pawel, additional, Maldonado, Rafael, additional, Bockaert, Joël, additional, Marin, Philippe, additional, and Bécamel, Carine, additional
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- 2022
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16. A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility
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Sheu, Shu-Hsien, primary, Upadhyayula, Srigokul, additional, Dupuy, Vincent, additional, Pang, Song, additional, Deng, Fei, additional, Wan, Jinxia, additional, Walpita, Deepika, additional, Pasolli, H. Amalia, additional, Houser, Justin, additional, Sanchez-Martinez, Silvia, additional, Brauchi, Sebastian E., additional, Banala, Sambashiva, additional, Freeman, Melanie, additional, Xu, C. Shan, additional, Kirchhausen, Tom, additional, Hess, Harald F., additional, Lavis, Luke, additional, Li, Yulong, additional, Chaumont-Dubel, Séverine, additional, and Clapham, David E., additional
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- 2022
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17. Impact of 5-HT 6 Receptor Subcellular Localization on Its Signaling and Its Pathophysiological Roles.
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Chaumont-Dubel, Séverine, Galant, Sonya, Prieur, Matthieu, Bouschet, Tristan, Bockaert, Joël, and Marin, Philippe
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SEROTONIN receptors , *CELL compartmentation , *CENTRAL nervous system , *CELLULAR signal transduction , *COGNITIVE ability , *CILIA & ciliary motion - Abstract
The serotonin (5-HT)6 receptor still raises particular interest given its unique spatio-temporal pattern of expression among the serotonin receptor subtypes. It is the only serotonin receptor specifically expressed in the central nervous system, where it is detected very early in embryonic life and modulates key neurodevelopmental processes, from neuronal migration to brain circuit refinement. Its predominant localization in the primary cilium of neurons and astrocytes is also unique among the serotonin receptor subtypes. Consistent with the high expression levels of the 5-HT6 receptor in brain regions involved in the control of cognitive processes, it is now well-established that the pharmacological inhibition of the receptor induces pro-cognitive effects in several paradigms of cognitive impairment in rodents, including models of neurodevelopmental psychiatric disorders and neurodegenerative diseases. The 5-HT6 receptor can engage several signaling pathways in addition to the canonical Gs signaling, but there is still uncertainty surrounding the signaling pathways that underly its modulation of cognition, as well as how the receptor's coupling is dependent on its cellular compartmentation. Here, we describe recent findings showing how the proper subcellular localization of the receptor is achieved, how this peculiar localization determines signaling pathways engaged by the receptor, and their pathophysiological influence. [ABSTRACT FROM AUTHOR]
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- 2023
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18. Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT 6 and D 3 R Affinity in the 1 H -Pyrrolo[3,2- c ]quinoline Series.
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Grychowska, Katarzyna, Pietruś, Wojciech, Kulawik, Ludmiła, Bento, Ophélie, Satała, Grzegorz, Bantreil, Xavier, Lamaty, Frédéric, Bojarski, Andrzej J., Gołębiowska, Joanna, Nikiforuk, Agnieszka, Marin, Philippe, Chaumont-Dubel, Séverine, Kurczab, Rafał, and Zajdel, Paweł
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G protein coupled receptors ,MOLECULAR dynamics ,RECEPTOR-ligand complexes ,QUINOLINE derivatives ,MOLECULAR interactions ,AMINES ,QUINOLINE - Abstract
Salt bridge (SB, double-charge-assisted hydrogen bonds) formation is one of the strongest molecular non-covalent interactions in biological systems, including ligand–receptor complexes. In the case of G-protein-coupled receptors, such an interaction is formed by the conserved aspartic acid (D3.32) residue and the basic moiety of the aminergic ligand. This study aims to determine the influence of the substitution pattern at the basic nitrogen atom and the geometry of the amine moiety at position 4 of 1H-pyrrolo[3,2-c]quinoline on the quality of the salt bridge formed in the 5-HT
6 receptor and D3 receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1H-pyrrolo[3,2-c]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT6 R affinity and more potent 5-HT6 R antagonist properties when compared with the previously identified compound PZ-1643, a dual-acting 5-HT6 R/D3 R antagonist; nevertheless, the proposed modifications did not improve the activity at D3 R. As demonstrated by the in silico experiments, including molecular dynamics simulations, the applied structural modifications were highly beneficial for the formation and quality of the SB formation at the 5-HT6 R binding site; however, they are unfavorable for such interactions at D3 R. [ABSTRACT FROM AUTHOR]- Published
- 2023
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19. 1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT 6 R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity.
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Canale, Vittorio, Trybała, Wojciech, Chaumont-Dubel, Séverine, Koczurkiewicz-Adamczyk, Paulina, Satała, Grzegorz, Bento, Ophélie, Blicharz-Futera, Klaudia, Bantreil, Xavier, Pękala, Elżbieta, Bojarski, Andrzej J., Lamaty, Frédéric, Marin, Philippe, and Zajdel, Paweł
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PIPERAZINE ,ADENYLATE cyclase ,CELLULAR signal transduction ,NEUROPLASTICITY ,NEURODEGENERATION ,NEURAL development - Abstract
In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT
6 R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT6 R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT6 R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT6 R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT6 R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]- Published
- 2023
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20. A serotonergic axon-cilium synapse drives nuclear signaling to maintain chromatin accessibility
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Sheu, Shu-Hsien, primary, Upadhyayula, Srigokul, additional, Dupuy, Vincent, additional, Pang, Song, additional, Lemire, Andrew L., additional, Walpita, Deepika, additional, Pasolli, H. Amalia, additional, Deng, Fei, additional, Wan, Jinxia, additional, Wang, Lihua, additional, Houser, Justin, additional, Sanchez-Martinez, Silvia, additional, Brauchi, Sebastian E., additional, Banala, Sambashiva, additional, Freeman, Melanie, additional, Xu, C. Shan, additional, Kirchhausen, Tom, additional, Hess, Harald F., additional, Lavis, Luke, additional, Li, Yu-Long, additional, Chaumont-Dubel, Séverine, additional, and Clapham, David E., additional
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- 2021
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21. Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties
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Zajdel, Paweł, primary, Grychowska, Katarzyna, additional, Mogilski, Szczepan, additional, Kurczab, Rafał, additional, Satała, Grzegorz, additional, Bugno, Ryszard, additional, Kos, Tomasz, additional, Gołębiowska, Joanna, additional, Malikowska-Racia, Natalia, additional, Nikiforuk, Agnieszka, additional, Chaumont-Dubel, Séverine, additional, Bantreil, Xavier, additional, Pawłowski, Maciej, additional, Martinez, Jean, additional, Subra, Gilles, additional, Lamaty, Frédéric, additional, Marin, Philippe, additional, Bojarski, Andrzej J., additional, and Popik, Piotr, additional
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- 2021
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22. Novel and atypical pathways for serotonin signaling
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Bockaert, Joël, primary, Bécamel, Carine, additional, Chaumont-Dubel, Séverine, additional, Claeysen, Sylvie, additional, Vandermoere, Franck, additional, and Marin, Philippe, additional
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- 2021
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23. 2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity
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Drop, Marcin, primary, Canale, Vittorio, additional, Chaumont-Dubel, Séverine, additional, Kurczab, Rafał, additional, Satała, Grzegorz, additional, Bantreil, Xavier, additional, Walczak, Maria, additional, Koczurkiewicz-Adamczyk, Paulina, additional, Latacz, Gniewomir, additional, Gwizdak, Anna, additional, Krawczyk, Martyna, additional, Gołębiowska, Joanna, additional, Grychowska, Katarzyna, additional, Bojarski, Andrzej J., additional, Nikiforuk, Agnieszka, additional, Subra, Gilles, additional, Martinez, Jean, additional, Pawłowski, Maciej, additional, Popik, Piotr, additional, Marin, Philippe, additional, Lamaty, Frédéric, additional, and Zajdel, Paweł, additional
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- 2021
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24. Amelioration of Tau pathology and memory deficits by targeting 5-HT7 receptor
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Labus, Josephine, primary, Röhrs, Kian-Fritz, additional, Ackmann, Jana, additional, Varbanov, Hristo, additional, Müller, Franziska E., additional, Jia, Shaobo, additional, Jahreis, Kathrin, additional, Vollbrecht, Anna-Lena, additional, Butzlaff, Malte, additional, Schill, Yvonne, additional, Guseva, Daria, additional, Böhm, Katrin, additional, Kaushik, Rahul, additional, Bijata, Monika, additional, Marin, Philippe, additional, Chaumont-Dubel, Séverine, additional, Zeug, Andre, additional, Dityatev, Alexander, additional, and Ponimaskin, Evgeni, additional
- Published
- 2021
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25. mTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its treatment
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Martin, Pierre-Yves, Doly, Stéphane, Hamieh, Al Mahdy, Chapuy, Eric, Canale, Vittorio, Drop, Marcin, Chaumont-Dubel, Séverine, Bantreil, Xavier, Lamaty, Frédéric, Bojarski, Andrzej, Zajdel, Pawel, Eschalier, Alain, Marin, Philippe, COURTEIX, Christine, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), ANR-17-CE16-0010,Sero6Dev,Réseau de signalisation associé au récepteur 5-HT6 et développement neuronal(2017), ANR-17-CE16-0013,StopSero6TOR,La signalisation mTOR induite par le récepteur 5-HT6 comme cible thérapeutique pour prévenir l'apparition des déficits cognitifs dans la schizophrénie(2017), ANR-19-CE18-0018,SERO6Pain,Les voies de signalisation du récepteur 5-HT6: de nouvelles cibles pour le traitement de la douleur neuropathique?(2019), COURTEIX, Christine, Réseau de signalisation associé au récepteur 5-HT6 et développement neuronal - - Sero6Dev2017 - ANR-17-CE16-0010 - AAPG2017 - VALID, La signalisation mTOR induite par le récepteur 5-HT6 comme cible thérapeutique pour prévenir l'apparition des déficits cognitifs dans la schizophrénie - - StopSero6TOR2017 - ANR-17-CE16-0013 - AAPG2017 - VALID, Les voies de signalisation du récepteur 5-HT6: de nouvelles cibles pour le traitement de la douleur neuropathique? - - SERO6Pain2019 - ANR-19-CE18-0018 - AAPG2019 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), and Université Clermont Auvergne (UCA)
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MESH: Cognitive Dysfunction/drug therapy ,Male ,Nociception ,MESH: Neuralgia/drug therapy ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,MESH: Hyperalgesia/drug therapy ,MESH: Rats, Sprague-Dawley ,MESH: Nociception/drug effects ,Neuropathic pain ,MESH: Neuralgia/complications ,Rats, Sprague-Dawley ,Serotonin Agents ,MESH: Animals ,MESH: Receptors, Serotonin/drug effects ,Neuropathic pain Cognitive deficit 5-HT6 receptor Constitutive activity mTOR Inverse agonist ,Behavior, Animal ,TOR Serine-Threonine Kinases ,MESH: Hyperalgesia/metabolism ,MESH: Cognitive Dysfunction/metabolism ,[SDV] Life Sciences [q-bio] ,MESH: Serotonin Agents/pharmacology ,Hyperalgesia ,MESH: HEK293 Cells ,mTOR ,MESH: Neuralgia/metabolism ,Inverse agonist ,MESH: Serotonin Agents/administration & dosage ,MESH: Behavior Animal/drug effects ,MESH: Rats ,MESH: Mice, Transgenic ,MESH: Cognitive Dysfunction/etiology ,Mice, Transgenic ,MESH: TOR Serine-Threonine Kinases/metabolism ,Constitutive activity ,MESH: Mice, Inbred C57BL ,Animals ,Humans ,Cognitive Dysfunction ,MESH: Humans ,Cognitive deficit ,MESH: Receptors, Serotonin/metabolism ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,MESH: TOR Serine-Threonine Kinases/drug effects ,MESH: Male ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,HEK293 Cells ,5-HT6 receptor ,Receptors, Serotonin ,Neuralgia ,MESH: Disease Models, Animal - Abstract
International audience; Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT6 receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT6 receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT6 receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT6 receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.
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- 2020
26. Early 5‐ HT 6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse
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Berthoux, Coralie, Hamieh, Al Mahdy, Rogliardo, Angelina, Doucet, Emilie L, Coudert, Camille, Ango, Fabrice, Grychowska, Katarzyna, Chaumont‐Dubel, Séverine, Zajdel, Pawel, Maldonado, Rafael, Bockaert, Joël, Marin, Philippe, Bécamel, Carine, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Department of Medicinal Chemistry, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Neuropharmacology Laboratory [Barcelone, Espagne], Universitat Pompeu Fabra [Barcelona] (UPF), Guerineau, Nathalie C., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Marijuana Abuse ,cognitive deficits ,5HT6 receptor ,[SDV]Life Sciences [q-bio] ,Prefrontal Cortex ,Articles ,Article ,[SDV] Life Sciences [q-bio] ,Mice ,Receptors, Serotonin ,Chemical Biology ,mTOR ,Animals ,adolescent cannabis abusers ,synaptic transmission ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Dronabinol ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Development & Differentiation ,Neuroscience - Abstract
Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5‐HT 6 receptor‐operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9‐tetrahydrocannabinol (THC) to mice during adolescence induces a long‐lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long‐term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5‐HT 6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5‐HT 6 receptor‐operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5‐HT 6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers., Early blockade of 5‐HT 6 receptor‐operated mTOR signaling could be a novel therapeutic strategy to prevent adult stage‐onset of cognitive deficits in cannabis abusers during adolescence.
- Published
- 2020
27. Early $5-HT_{6}$ receptor blockade prevents symptom onset in a model of adolescent cannabis abuse
- Author
-
Berthoux, Coralie, Hamieh, Al Mahdy, Rogliardo, Angelina, Doucet, Emilie L., Coudert, Camille, Ango, Fabrice, Grychowska, Katarzyna, Chaumont-Dubel, Séverine, Zajdel, Pawel, Maldonado, Rafael, 1961, Bockaert, Joël, Marin, Philippe, and Bécamel, Carine
- Subjects
Medicine (General) ,cognitive deficits ,R5-920 ,5HT6 receptor ,$5HT_{6}$ receptor ,Genetics ,mTOR ,adolescent cannabis abusers ,synaptic transmission ,QH426-470 - Abstract
Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of $5-HT_{6}$ receptor-operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of $\Delta9$-tetrahydrocannabinol (THC) to mice during adolescence induces a longlasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long-term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a $5-HT_{6}$ receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of $5-HT_{6}$ receptor-operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of $5-HT_{6}$ receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers.
- Published
- 2020
28. The 5-HT6 receptor interactome: New insight in receptor signaling and its impact on brain physiology and pathologies
- Author
-
Chaumont-Dubel, Séverine, primary, Dupuy, Vincent, additional, Bockaert, Joël, additional, Bécamel, Carine, additional, and Marin, Philippe, additional
- Published
- 2020
- Full Text
- View/download PDF
29. Dynamic interactions of the 5-HT6receptor with protein partners control dendritic tree morphogenesis
- Author
-
Pujol, Camille N., primary, Dupuy, Vincent, additional, Séveno, Martial, additional, Runtz, Leonie, additional, Bockaert, Joël, additional, Marin, Philippe, additional, and Chaumont-Dubel, Séverine, additional
- Published
- 2020
- Full Text
- View/download PDF
30. Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3and 5-HT6Receptor Antagonist with Antipsychotic and Procognitive Properties
- Author
-
Zajdel, Paweł, Grychowska, Katarzyna, Mogilski, Szczepan, Kurczab, Rafał, Satała, Grzegorz, Bugno, Ryszard, Kos, Tomasz, Gołębiowska, Joanna, Malikowska-Racia, Natalia, Nikiforuk, Agnieszka, Chaumont-Dubel, Séverine, Bantreil, Xavier, Pawłowski, Maciej, Martinez, Jean, Subra, Gilles, Lamaty, Frédéric, Marin, Philippe, Bojarski, Andrzej J., and Popik, Piotr
- Abstract
In line with recent clinical trials demonstrating that ondansetron, a 5-HT3receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQshows selectivity over 87 targets and decent brain penetration. Likewise, FPPQinhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.
- Published
- 2021
- Full Text
- View/download PDF
31. Early 5‐HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse.
- Author
-
Berthoux, Coralie, Hamieh, Al Mahdy, Rogliardo, Angelina, Doucet, Emilie L, Coudert, Camille, Ango, Fabrice, Grychowska, Katarzyna, Chaumont‐Dubel, Séverine, Zajdel, Pawel, Maldonado, Rafael, Bockaert, Joël, Marin, Philippe, and Bécamel, Carine
- Abstract
Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5‐HT6 receptor‐operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9‐tetrahydrocannabinol (THC) to mice during adolescence induces a long‐lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long‐term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5‐HT6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5‐HT6 receptor‐operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5‐HT6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers. Synopsis: Early blockade of 5‐HT6 receptor‐operated mTOR signaling could be a novel therapeutic strategy to prevent adult stage‐onset of cognitive deficits in cannabis abusers during adolescence. A long‐lasting 5‐HT6 receptor‐operated mTOR activation is induced in prefrontal cortex of adult mice following chronic administration of THC during adolescence.This non‐physiological mTOR activation causes alterations of intrinsic properties of pyramidal neurons, E/I imbalance, impairment of LTD and cognitive deficits in adulthood.All these changes are prevented by the administration of 5‐HT6 receptor antagonists or rapamycin during adolescence. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
32. Dynamic interactions of the 5-HT6 receptor with protein partners control dendritic tree morphogenesis.
- Author
-
Pujol, Camille N., Dupuy, Vincent, Séveno, Martial, Runtz, Leonie, Bockaert, Joël, Marin, Philippe, and Chaumont-Dubel, Séverine
- Subjects
CYCLIC-AMP-dependent protein kinase ,ALLOSTERIC regulation ,PROTEIN receptors ,SEROTONIN receptors ,NEURONAL differentiation ,NEUROLOGICAL disorders ,G proteins - Abstract
Taking the time to signal: The serotonin receptor 5-HT
6 R is a GPCR exclusively found in the nervous system that has emerged as a potential therapeutic target in various neurological disorders. Although preliminary studies suggested that 5-HT6 R antagonists have procognitive effects, clinical trials have been disappointing. Pujol et al. analyzed the dynamics of 5-HT6 R interactions with other proteins and found that after its previously characterized interaction with and phosphorylation by the kinase Cdk5, the 5-HT6 R interacted with GPRIN1, a promoter of neurite extension. These sequential interactions enhanced 5-HT6 R constitutive activity, promoting neurite extension and branching in neuroblastoma cells and primary striatal neurons. The GPRIN1–5-HT6 R interaction was reduced by 5-HT6 R antagonist, suggesting that the dynamic interactions of this receptor are regulated by its conformational state. The serotonin (5-hydroxytrypatmine) receptor 5-HT6 (5-HT6 R) has emerged as a promising target to alleviate the cognitive symptoms of neurodevelopmental diseases. We previously demonstrated that 5-HT6 R finely controls key neurodevelopmental steps, including neuronal migration and the initiation of neurite growth, through its interaction with cyclin-dependent kinase 5 (Cdk5). Here, we showed that 5-HT6 R recruited G protein–regulated inducer of neurite outgrowth 1 (GPRIN1) through a Gs -dependent mechanism. Interactions between the receptor and either Cdk5 or GPRIN1 occurred sequentially during neuronal differentiation. The 5-HT6 R–GPRIN1 interaction enhanced agonist-independent, receptor-stimulated cAMP production without altering the agonist-dependent response in NG108-15 neuroblastoma cells. This interaction also promoted neurite extension and branching in NG108-15 cells and primary mouse striatal neurons through a cAMP-dependent protein kinase A (PKA)–dependent mechanism. This study highlights the complex allosteric modulation of GPCRs by protein partners and demonstrates how dynamic interactions between GPCRs and their protein partners can control the different steps of highly coordinated cellular processes, such as dendritic tree morphogenesis. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
33. Novel non-sulfonamide 5-HT 6 receptor partial inverse agonist in a group of imidazo[4,5- b ]pyridines with cognition enhancing properties
- Author
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Vanda, David, primary, Soural, Miroslav, additional, Canale, Vittorio, additional, Chaumont-Dubel, Séverine, additional, Satała, Grzegorz, additional, Kos, Tomasz, additional, Funk, Petr, additional, Fülöpová, Veronika, additional, Lemrová, Barbora, additional, Koczurkiewicz, Paulina, additional, Pękala, Elżbieta, additional, Bojarski, Andrzej J., additional, Popik, Piotr, additional, Marin, Philippe, additional, and Zajdel, Paweł, additional
- Published
- 2018
- Full Text
- View/download PDF
34. Physical interaction between neurofibromin and serotonin 5-HT 6 receptor promotes receptor constitutive activity
- Author
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Deraredj Nadim, Wissem, primary, Chaumont-Dubel, Séverine, additional, Madouri, Fahima, additional, Cobret, Laetitia, additional, De Tauzia, Marie-Ludivine, additional, Zajdel, Pawel, additional, Bénédetti, Hélène, additional, Marin, Philippe, additional, and Morisset-Lopez, Séverine, additional
- Published
- 2016
- Full Text
- View/download PDF
35. Early 5‐HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse.
- Author
-
Berthoux, Coralie, Hamieh, Al Mahdy, Rogliardo, Angelina, Doucet, Emilie L, Coudert, Camille, Ango, Fabrice, Grychowska, Katarzyna, Chaumont‐Dubel, Séverine, Zajdel, Pawel, Maldonado, Rafael, Bockaert, Joël, Marin, Philippe, and Bécamel, Carine
- Published
- 2022
- Full Text
- View/download PDF
36. 5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits
- Author
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Dayer, Alexandre G., primary, Jacobshagen, Moritz, additional, Chaumont-Dubel, Séverine, additional, and Marin, Philippe, additional
- Published
- 2015
- Full Text
- View/download PDF
37. Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity.
- Author
-
Nadim, Wissem Deraredj, Madouri, Fahima, Cobret, Laetitia, De Tauzia, Marie-Ludivine, Bénédetti, Hélène, Morisset-Lopez, Séverine, Chaumont-Dubel, Séverine, Marin, Philippe, and Zajdel, Pawel
- Subjects
NEUROFIBROMIN ,SEROTONIN receptors ,CHEMICAL agonists ,NERVOUS system cancer ,COGNITION disorders - Abstract
Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT
6 ) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/- mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/- mice. Collectively, these findings suggest that disrupting 5-HT6 receptor-neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
38. Superiority of the Triple-Acting 5-HT 6 R/5-HT 3 R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT 6 R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats.
- Author
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Grychowska K, López-Sánchez U, Vitalis M, Canet G, Satała G, Olejarz-Maciej A, Gołębiowska J, Kurczab R, Pietruś W, Kubacka M, Moreau C, Walczak M, Blicharz-Futera K, Bento O, Bantreil X, Subra G, Bojarski AJ, Lamaty F, Becamel C, Zussy C, Chaumont-Dubel S, Popik P, Nury H, Marin P, Givalois L, and Zajdel P
- Subjects
- Rats, Animals, Cryoelectron Microscopy, Receptors, Serotonin, Serotonin Antagonists pharmacology, Serotonin Antagonists therapeutic use, Monoamine Oxidase, Cognition, Monoamine Oxidase Inhibitors pharmacology, Monoamine Oxidase Inhibitors therapeutic use, Serotonin adverse effects, Alzheimer Disease drug therapy, Alzheimer Disease chemically induced
- Abstract
The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT
6 R antagonism and interaction with 5-HT3 R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT6 R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922 , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT6 R/5-HT3 R/MAO-B in AD.- Published
- 2023
- Full Text
- View/download PDF
39. Spatiotemporal dynamics of 5-HT 6 receptor ciliary localization during mouse brain development.
- Author
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Dupuy V, Prieur M, Pizzoccaro A, Margarido C, Valjent E, Bockaert J, Bouschet T, Marin P, and Chaumont-Dubel S
- Subjects
- Mice, Animals, Brain metabolism, Mice, Transgenic, Serotonin metabolism, Neurons metabolism
- Abstract
The serotonin 5-HT
6 receptor (5-HT6 R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT6 R. Here, we used transgenic mice expressing a GFP-tagged 5-HT6 R under the control of its endogenous promoter (Knock-in) as well as embryonic stem cells expressing the GFP-tagged receptor to extensively characterize its expression at cellular and subcellular levels during development. We show that the receptor is already expressed at E13.5 in the cortex, the striatum, the ventricular zone, and to a lesser extent the subventricular zone. In adulthood, it is preferentially found in projection neurons of the hippocampus and cerebral cortex, in striatal medium-sized spiny neurons, as well as in a large proportion of astrocytes, while it is expressed in a minor population of interneurons. Whereas the receptor is almost exclusively detected in the primary cilia of neurons at embryonic and adult stages and in differentiated stem cells, it is located in the somatodendritic compartment of neurons from some brain regions at the neonatal stage and in the soma of undifferentiated stem cells. Finally, knocking-out the receptor induces a shortening of the primary cilium, suggesting that it plays a role in its function. This study provides the first global picture of 5-HT6 R expression pattern in the mouse brain at different developmental stages. It reveals dynamic changes in receptor localization in neurons at the neonatal stage, which might underlie its key role in neuronal differentiation and psychiatric disorders of neurodevelopmental origin., Competing Interests: Declaration of Competing Interest The authors declare they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
40. 1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT 6 R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity.
- Author
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Canale V, Trybała W, Chaumont-Dubel S, Koczurkiewicz-Adamczyk P, Satała G, Bento O, Blicharz-Futera K, Bantreil X, Pękala E, Bojarski AJ, Lamaty F, Marin P, and Zajdel P
- Subjects
- Ligands, Cognition, Piperazines pharmacology, Serotonin pharmacology, Drug Inverse Agonism
- Abstract
In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT
6 R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT6 R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT6 R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g , which behaves as a neutral antagonist at the 5-HT6 R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT6 R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases.- Published
- 2022
- Full Text
- View/download PDF
41. Early 5-HT 6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse.
- Author
-
Berthoux C, Hamieh AM, Rogliardo A, Doucet EL, Coudert C, Ango F, Grychowska K, Chaumont-Dubel S, Zajdel P, Maldonado R, Bockaert J, Marin P, and Bécamel C
- Published
- 2022
- Full Text
- View/download PDF
42. Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT 3 and 5-HT 6 Receptor Antagonist with Antipsychotic and Procognitive Properties.
- Author
-
Zajdel P, Grychowska K, Mogilski S, Kurczab R, Satała G, Bugno R, Kos T, Gołębiowska J, Malikowska-Racia N, Nikiforuk A, Chaumont-Dubel S, Bantreil X, Pawłowski M, Martinez J, Subra G, Lamaty F, Marin P, Bojarski AJ, and Popik P
- Subjects
- Animals, Antipsychotic Agents chemical synthesis, Antipsychotic Agents metabolism, Antipsychotic Agents pharmacokinetics, Drug Combinations, Guinea Pigs, Humans, Male, Microsomes, Liver metabolism, Molecular Structure, Nootropic Agents chemical synthesis, Nootropic Agents metabolism, Nootropic Agents pharmacokinetics, Ondansetron therapeutic use, Piperazines therapeutic use, Rats, Rats, Sprague-Dawley, Serotonin 5-HT3 Receptor Antagonists chemical synthesis, Serotonin 5-HT3 Receptor Antagonists metabolism, Serotonin 5-HT3 Receptor Antagonists pharmacokinetics, Structure-Activity Relationship, Sulfonamides therapeutic use, Antipsychotic Agents therapeutic use, Cognitive Dysfunction drug therapy, Nootropic Agents therapeutic use, Receptors, Serotonin metabolism, Receptors, Serotonin, 5-HT3 metabolism, Serotonin 5-HT3 Receptor Antagonists therapeutic use
- Abstract
In line with recent clinical trials demonstrating that ondansetron, a 5-HT
3 receptor (5-HT3 R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6 R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3 /5-HT6 R antagonists. We identified the first-in-class compound FPPQ , which behaves as a 5-HT3 R antagonist and a neutral antagonist 5-HT6 R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ , neither 5-HT6 R inverse agonist SB399885 nor neutral 5-HT6 R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3 R antagonism and 5-HT6 R antagonism, exemplified by FPPQ , contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3 /5-HT6 receptors and encourage further studies on dual-acting 5-HT3 /5-HT6 R antagonists for the treatment of psychiatric disorders.- Published
- 2021
- Full Text
- View/download PDF
43. 2-Phenyl-1 H -pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT 6 Receptor Inverse Agonists with Cognition-Enhancing Activity.
- Author
-
Drop M, Canale V, Chaumont-Dubel S, Kurczab R, Satała G, Bantreil X, Walczak M, Koczurkiewicz-Adamczyk P, Latacz G, Gwizdak A, Krawczyk M, Gołębiowska J, Grychowska K, Bojarski AJ, Nikiforuk A, Subra G, Martinez J, Pawłowski M, Popik P, Marin P, Lamaty F, and Zajdel P
- Subjects
- Animals, Cognition, Rats, Structure-Activity Relationship, Pyrroles pharmacology, Receptors, Serotonin
- Abstract
Serotonin type 6 receptor (5-HT
6 R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1 H -pyrrolo[3,2- c ]quinoline scaffold to provide the 2-phenyl-1 H -pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6 R. This modification has changed the compound's activity at 5-HT6 R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6 R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1 H -pyrrole-3-carboxamide might be used as a template for designing 5-HT6 R inverse agonists.- Published
- 2021
- Full Text
- View/download PDF
44. mTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its treatment.
- Author
-
Martin PY, Doly S, Hamieh AM, Chapuy E, Canale V, Drop M, Chaumont-Dubel S, Bantreil X, Lamaty F, Bojarski AJ, Zajdel P, Eschalier A, Marin P, and Courteix C
- Subjects
- Animals, Behavior, Animal drug effects, Disease Models, Animal, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Rats, Rats, Sprague-Dawley, Serotonin Agents administration & dosage, Cognitive Dysfunction drug therapy, Cognitive Dysfunction etiology, Cognitive Dysfunction metabolism, Hyperalgesia drug therapy, Hyperalgesia metabolism, Neuralgia complications, Neuralgia drug therapy, Neuralgia metabolism, Nociception drug effects, Receptors, Serotonin drug effects, Receptors, Serotonin metabolism, Serotonin Agents pharmacology, TOR Serine-Threonine Kinases drug effects, TOR Serine-Threonine Kinases metabolism
- Abstract
Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT
6 receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT6 receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT6 receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT6 receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
45. The 5-HT 6 receptor interactome: New insight in receptor signaling and its impact on brain physiology and pathologies.
- Author
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Chaumont-Dubel S, Dupuy V, Bockaert J, Bécamel C, and Marin P
- Subjects
- Animals, Humans, Serotonin Antagonists pharmacology, Brain physiology, Brain physiopathology, Receptors, Serotonin drug effects, Serotonin Agents pharmacology, Signal Transduction
- Abstract
The serotonin (5-HT)
6 receptor is a Gs-coupled receptor exclusively expressed in the central nervous system. Highest receptor densities are found in brain regions implicated in mnemonic functions where the receptor is primarily but not exclusively located in the primary cilium of neurons. The 5-HT6 receptor continues to raise particular interest for neuropharmacologists, given the pro-cognitive effects of antagonists in a wide range of cognitive impairment paradigms in rodents and human. The 5-HT6 receptor also finely controls key neuro-developmental processes including neuron migration and differentiation. However, its influence upon neurodevelopment and cognition is not solely mediated by its coupling to the Gs-adenylyl cyclase pathway, suggesting alternative signal transduction mechanisms. This prompted studies aimed at characterizing the receptor interactome that identified 125 candidate receptor partners, making the 5-HT6 receptor one of the G protein-coupled receptors with the most extensively characterized interactome. These studies showed that the receptor localization at the plasma membrane and, consequently, its signal transduction, are finely modulated by several receptor partners. They demonstrated that prefrontal 5-HT6 receptors engage the mTOR pathway to compromise cognition in neurodevelopmental models of schizophrenia, and a role of the 5-HT6 -mTOR pathway in temporal epilepsy. Finally, they revealed that the receptor activates Cdk5 signaling in an agonist-independent manner through a mechanism involving receptor phosphorylation by the associated Cdk5 and highlighted its key role in the migration of neurons and neurite growth. These new receptor-operated signaling mechanisms should be considered in the future development of drugs acting on 5-HT6 receptors. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'., Competing Interests: Declaration of competing interest The authors declare no competing interest with the present article., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
46. Early 5-HT 6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse.
- Author
-
Berthoux C, Hamieh AM, Rogliardo A, Doucet EL, Coudert C, Ango F, Grychowska K, Chaumont-Dubel S, Zajdel P, Maldonado R, Bockaert J, Marin P, and Bécamel C
- Subjects
- Animals, Dronabinol, Mice, Prefrontal Cortex, Receptors, Serotonin, Marijuana Abuse
- Abstract
Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5-HT
6 receptor-operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9-tetrahydrocannabinol (THC) to mice during adolescence induces a long-lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long-term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5-HT6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5-HT6 receptor-operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5-HT6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2020
- Full Text
- View/download PDF
47. Dynamic interactions of the 5-HT 6 receptor with protein partners control dendritic tree morphogenesis.
- Author
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Pujol CN, Dupuy V, Séveno M, Runtz L, Bockaert J, Marin P, and Chaumont-Dubel S
- Subjects
- Animals, Cell Line, Tumor, Cell Movement, Cyclic AMP-Dependent Protein Kinases metabolism, Cyclin-Dependent Kinase 5 genetics, Cyclin-Dependent Kinase 5 metabolism, Mice, Morphogenesis, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neurites metabolism, Neurons cytology, Neurons metabolism, Protein Binding, Receptors, N-Methyl-D-Aspartate genetics, Receptors, N-Methyl-D-Aspartate metabolism, Receptors, Serotonin genetics, Cyclic AMP metabolism, Dendrites metabolism, Receptors, Serotonin metabolism, Signal Transduction
- Abstract
The serotonin (5-hydroxytrypatmine) receptor 5-HT
6 (5-HT6 R) has emerged as a promising target to alleviate the cognitive symptoms of neurodevelopmental diseases. We previously demonstrated that 5-HT6 R finely controls key neurodevelopmental steps, including neuronal migration and the initiation of neurite growth, through its interaction with cyclin-dependent kinase 5 (Cdk5). Here, we showed that 5-HT6 R recruited G protein-regulated inducer of neurite outgrowth 1 (GPRIN1) through a Gs -dependent mechanism. Interactions between the receptor and either Cdk5 or GPRIN1 occurred sequentially during neuronal differentiation. The 5-HT6 R-GPRIN1 interaction enhanced agonist-independent, receptor-stimulated cAMP production without altering the agonist-dependent response in NG108-15 neuroblastoma cells. This interaction also promoted neurite extension and branching in NG108-15 cells and primary mouse striatal neurons through a cAMP-dependent protein kinase A (PKA)-dependent mechanism. This study highlights the complex allosteric modulation of GPCRs by protein partners and demonstrates how dynamic interactions between GPCRs and their protein partners can control the different steps of highly coordinated cellular processes, such as dendritic tree morphogenesis., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
- Full Text
- View/download PDF
48. Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity.
- Author
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Deraredj Nadim W, Chaumont-Dubel S, Madouri F, Cobret L, De Tauzia ML, Zajdel P, Bénédetti H, Marin P, and Morisset-Lopez S
- Subjects
- Adenylyl Cyclases genetics, Adenylyl Cyclases metabolism, Animals, Cyclic AMP metabolism, Disease Models, Animal, Gene Expression Regulation genetics, Humans, Mice, Mice, Knockout, Mutation, Neurofibromatosis 1 pathology, Neurofibromin 1 metabolism, Neurons metabolism, Neurons pathology, Phosphorylation, Pleckstrin Homology Domains genetics, Prefrontal Cortex drug effects, Prefrontal Cortex pathology, Serotonin genetics, Neurofibromatosis 1 genetics, Neurofibromin 1 genetics, Receptors, Serotonin genetics, Serotonin metabolism
- Abstract
Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT
6 ) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/- mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/- mice. Collectively, these findings suggest that disrupting 5-HT6 receptor-neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients., Competing Interests: The authors declare no conflict of interest.- Published
- 2016
- Full Text
- View/download PDF
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