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Biomolecules
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Recent Advances on 5-HT6 Receptors
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Recent Advances on 5-HT6 Receptors

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 7744

Special Issue Editors

Prof. Dr. Philippe De Deurwaerdere

E-Mail Website
Guest Editor
Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5287), 33076 Bordeaux CEDEX, France
Interests: monoamines; neurochemistry; addiction; Parkinson's disease; schizophrenia; neuropharmacology; mood disorders
Special Issues, Collections and Topics in MDPI journals
Dr. Abdeslam Chagraoui

E-Mail Website
Guest Editor
Department of Medical Biochemistry, Rouen University Hospital, 76000 Rouen, France
Interests: monoamines; neurochemistry; neuropharmacology; neuropsychopharmacology; mood disorders; addiction; Parkinson's disease and Schizophrenia
Special Issues, Collections and Topics in MDPI journals
Dr. Séverine Chaumont-Dubel

E-Mail Website1 Website2
Guest Editor
Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
Interests: 5-HT6 receptor; serotonin; constitutive activity; neurodevelopment. proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The 5-HT6 receptor is one of the most recently discovered 5-HT receptors, and it is mostly expressed in regions of the central nervous system that are involved in cognitive functions. Probably some of the most intriguing roles of this receptor concern development, nociception, and cognition. It has one of the most extensively characterized GPCR interactomes to date. Its protein partners not only connect it to multiple intracellular signaling pathways but also control its strong constitutive activity. There is a great deal of interest concerning its specific compartmentalization in neurons, notably the primary cilium. Finally, numerous studies have demonstrated that the 5-HT6 receptor antagonists improve cognition in several models of cognitive impairments, raising new interest in the development of specific 5-HT6 receptor ligands. This receptor has therefore emerged as a promising target for the treatment of the cognitive deficits found in various neuropsychiatric diseases either as a single target or via multitarget approaches (D3, 5-HT2A, 5-HT3 receptors, etc.). The 5-HT6 receptor is definitely an original receptor, but there is still a lot to discover to provide a complete picture of its key pathophysiological roles. We propose to collect research articles or review articles on this peculiar receptor belonging to the numerous fields of biology and medicine.

Prof. Dr. Philippe De Deurwaerdere
Dr. Abdeslam Chagraoui
Dr. Séverine Chaumont-Dubel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular partners
  • cognition
  • development
  • nociception
  • multitarget drug
  • constitutive activity
  • pharmacology
  • chemistry

Published Papers (4 papers)

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Research

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12 pages, 1509 KiB  
Article
5-HT6 Receptors Sex-Dependently Modulate Hippocampal Synaptic Activity through GABA Inhibition
by Caroline Lahogue, Jean-Marie Billard, Thomas Freret and Valentine Bouet
Biomolecules 2023, 13(5), 751; https://doi.org/10.3390/biom13050751 - 26 Apr 2023
Viewed by 1017
Abstract
The subtype 6 of the serotoninergic receptors (5-HT6Rs) is highly expressed in the hippocampus, and evidence indicates the beneficial effects of 5-HT6Rs blockade on short- and long-term memory in rodents. Nevertheless, the underlying functional mechanisms still need to be established. To this end, [...] Read more.
The subtype 6 of the serotoninergic receptors (5-HT6Rs) is highly expressed in the hippocampus, and evidence indicates the beneficial effects of 5-HT6Rs blockade on short- and long-term memory in rodents. Nevertheless, the underlying functional mechanisms still need to be established. To this end, we performed electrophysiological extracellular recordings to assess the effects of the 5-HT6Rs antagonist SB-271046 on the synaptic activity and functional plasticity at the CA3/CA1 hippocampal connections of male and female mice slices. We found that basal excitatory synaptic transmission and isolated N-methyl-D-aspartate receptors (NMDARs) activation were significantly increased by SB-271046. The NMDARs-related improvement was prevented by the GABAAR antagonist bicuculline in male but not in female mice. Regarding synaptic plasticity, neither paired-pulse facilitation (PPF) nor NMDARs-dependent long-term potentiation (LTP) (induced either by high-frequency or theta-burst stimulation) was affected by the 5-HT6Rs blockade. Taken together, our results indicate a sex-dependent 5-HT6Rs effect on synaptic activity at the CA3/CA1 hippocampal connections through changes in the excitation/inhibition balance. Full article
(This article belongs to the Special Issue Recent Advances on 5-HT6 Receptors)
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17 pages, 3830 KiB  
Article
The Constitutive Activity of Spinal 5-HT6 Receptors Contributes to Diabetic Neuropathic Pain in Rats
by Nazarine Mokhtar, Marcin Drop, Florian Jacquot, Sylvain Lamoine, Eric Chapuy, Laetitia Prival, Youssef Aissouni, Vittorio Canale, Frédéric Lamaty, Paweł Zajdel, Philippe Marin, Stéphane Doly and Christine Courteix
Biomolecules 2023, 13(2), 364; https://doi.org/10.3390/biom13020364 - 15 Feb 2023
Cited by 1 | Viewed by 1622
Abstract
Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT6) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the [...] Read more.
Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT6) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the involvement of 5-HT6 receptor constitutive activity and mTOR signaling in an experimental model of diabetic neuropathic pain induced by streptozocin (STZ) injection in the rat. Here, we show that mechanical hyperalgesia and associated cognitive deficits are suppressed by the administration of 5-HT6 receptor inverse agonists or rapamycin. The 5-HT6 receptor ligands also reduced tactile allodynia in traumatic and toxic neuropathic pain induced by spinal nerve ligation and oxaliplatin injection. Furthermore, both painful and co-morbid cognitive symptoms in diabetic rats are reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor-mTOR physical interaction. These findings demonstrate the deleterious influence of the constitutive activity of spinal 5-HT6 receptors upon painful and cognitive symptoms in diabetic 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 diabetic neuropathic pain and cognitive co-morbidities. Full article
(This article belongs to the Special Issue Recent Advances on 5-HT6 Receptors)
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16 pages, 2554 KiB  
Article
1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity
by Vittorio Canale, Wojciech Trybała, Séverine Chaumont-Dubel, Paulina Koczurkiewicz-Adamczyk, Grzegorz Satała, Ophélie Bento, Klaudia Blicharz-Futera, Xavier Bantreil, Elżbieta Pękala, Andrzej J. Bojarski, Frédéric Lamaty, Philippe Marin and Paweł Zajdel
Biomolecules 2023, 13(1), 12; https://doi.org/10.3390/biom13010012 - 21 Dec 2022
Cited by 3 | Viewed by 2027
Abstract
In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT6R) 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 [...] Read more.
In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT6R) 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-HT6R-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-HT6R-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-HT6R-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-HT6R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Recent Advances on 5-HT6 Receptors)
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Review

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19 pages, 700 KiB  
Review
Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders
by Ramakrishna Nirogi, Pradeep Jayarajan, Anil Shinde, Abdul Rasheed Mohammed, Venkata Ramalingayya Grandhi, Vijay Benade, Vinod Kumar Goyal, Renny Abraham, Venkat Jasti and Jeffrey Cummings
Biomolecules 2023, 13(2), 309; https://doi.org/10.3390/biom13020309 - 07 Feb 2023
Cited by 11 | Viewed by 2195
Abstract
Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor [...] Read more.
Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer’s disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer’s type. Full article
(This article belongs to the Special Issue Recent Advances on 5-HT6 Receptors)
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