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Pharmaceuticals
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Molecular Pharmacology of 5-HT Receptors
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Molecular Pharmacology of 5-HT Receptors

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (25 January 2022) | Viewed by 26585

Special Issue Editor

Dr. Caroline Sevoz-Couche

E-Mail Website
Guest Editor
Sorbonne Universite, Paris, France
Interests: autonomic; stress; vagal; serotonin; respiration

Special Issue Information

Dear Colleagues,

Neurotransmitter receptors are essential for mediating the effects of neurotransmitters in the brain and peripheral nervous system. There are generally considered to be two types of neurotransmitter receptors: ionotropic and metabotropic. While ionotropic receptors are typically ligand-gated ion channels (LGICs), through which ions pass in response to a neurotransmitter, metabotropic receptors need G proteins and second messengers to indirectly modulate ionic activity in neurons (GPCRs). Serotonin (5-hydroxytryptamine, 5-HT) is probably unique among monoamines in that its effects are subserved by as many as 13 distinct heptahelical GPCRs (5HT1,2,4,5,6, and 7 receptors) and one LGIC (5-HT3 receptor).  

In the human central nervous system (CNS) alone, all the serotonin receptor subtypes, with the exception of 5-HT5b, are expressed. LGICs require auxiliary subunits for their trafficking, assembly, and pharmacological modulation. Auxiliary subunits do not form functional homomeric receptors but are reported to assemble with the principal subunits in order to modulate their pharmacological profiles. For example, in the brain, serotonergic 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E are reported to assemble with the 5-HT3A subunit to modulate its pharmacological profile.

GPCR structures have been historically challenging. To generate useful structures, high-affinity ligands are required to stabilize the receptor in a distinct state suitable for crystallography. Once crystallography structures are obtained, features for distinct pharmacological properties can be elucidated. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptors.

Much research regarding serotonin has been in the area of neuropsychiatric drug discovery in the treatment of affective disorders, where there continues to be an extreme interest in the design of more efficacious pharmaceuticals. With the wealth of structural information obtained in the past twenty years for serotonin GPCRs and LPGCs, this Special Issue focuses on the challenge for modern 5-HT research: structure-guided approaches that eventually lead to neuropsychiatric medications with greater efficacy and fewer side effects.

Dr. Caroline Sevoz-Couche
Guest Editor

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. Pharmaceuticals 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 2900 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

  • serotonin
  • structure
  • neuropsychiatric drug
  • stress

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Published Papers (6 papers)

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Research

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16 pages, 3066 KiB  
Article
Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT1A Receptor Biased Agonist
by Sharon Cabanu, Fuencisla Pilar-Cuéllar, Paula Zubakina, Eva Florensa-Zanuy, Júlia Senserrich, Adrian Newman-Tancredi and Albert Adell
Pharmaceuticals 2022, 15(3), 337; https://doi.org/10.3390/ph15030337 - 10 Mar 2022
Cited by 5 | Viewed by 4808
Abstract
Depression is the most prevalent of the mental illnesses and serotonin (5-hydroxytryptamine, 5-HT) is considered to be the major neurotransmitter involved in its etiology and treatment. In this context, 5-HT1A receptors have attracted interest as targets for therapeutic intervention. Notably the activation [...] Read more.
Depression is the most prevalent of the mental illnesses and serotonin (5-hydroxytryptamine, 5-HT) is considered to be the major neurotransmitter involved in its etiology and treatment. In this context, 5-HT1A receptors have attracted interest as targets for therapeutic intervention. Notably the activation of presynaptic 5-HT1A autoreceptors delays antidepressant effects whereas the stimulation of postsynaptic 5-HT1A heteroreceptors is needed for an antidepressant action. NLX-101 (also known as F15599) is a selective biased agonist which exhibits preferred activation of cortical over brain stem 5-HT1A receptors. Here, we used behavioral, neurochemical and molecular methods to examine the antidepressant-like effects in rats of a single dose of NLX-101 (0.16 mg/kg, i.p.). NLX-101 reduced immobility in the forced swim test when measured 30 min but not 24 h after drug administration. NLX-101 increased extracellular concentrations of glutamate and dopamine in the medial prefrontal cortex, but no changes were detected in the efflux of noradrenaline or 5-HT. NLX-101 also produced an increase in the activation of pmTOR, pERK1/2 and pAkt, and the expression of PSD95 and GluA1, which may contribute to its rapid antidepressant action. Full article
(This article belongs to the Special Issue Molecular Pharmacology of 5-HT Receptors)
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32 pages, 2748 KiB  
Article
Novel N-Arylsulfonylindoles Targeted as Ligands of the 5-HT6 Receptor. Insights on the Influence of C-5 Substitution on Ligand Affinity
by Loreto Arrieta-Rodríguez, Daniela Espinoza-Rosales, Gonzalo Vera, Young Hwa Cho, David Cabezas, David Vásquez-Velásquez, Jaime Mella-Raipán, Carlos F. Lagos and Gonzalo Recabarren-Gajardo
Pharmaceuticals 2021, 14(6), 528; https://doi.org/10.3390/ph14060528 - 1 Jun 2021
Cited by 1 | Viewed by 2957
Abstract
A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (Ki = 58–403 nM), with [...] Read more.
A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (Ki = 58–403 nM), with compound 4d being identified as the most potent ligand. However, regarding C-5 substitution, both methoxy and fluorine were detrimental for receptor affinity compared to our previously published unsubstituted compounds. In order to shed light on these observations, we performed docking and molecular dynamics simulations with the most potent compounds of each series (4d and 4l) and PUC-10, a highly active ligand previously reported by our group. The comparison brings about deeper insight about the influence of the C-5 substitution on the binding mode of the ligands, suggesting that these replacements are detrimental to the affinity due to precluding a ligand from reaching deeper inside the binding site. Additionally, CoMFA/CoMSIA studies were performed to systematize the information of the main structural and physicochemical characteristics of the ligands, which are responsible for their biological activity. The CoMFA and CoMSIA models presented high values of q2 (0.653; 0.692) and r2 (0.879; 0.970), respectively. Although the biological activity of the ligands can be explained in terms of the steric and electronic properties, it depends mainly on the electronic nature. Full article
(This article belongs to the Special Issue Molecular Pharmacology of 5-HT Receptors)
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28 pages, 2579 KiB  
Article
Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HT1A Serotonin Receptor Antagonists
by Kinga Ostrowska, Anna Leśniak, Zuzanna Czarnocka, Jagoda Chmiel, Magdalena Bujalska-Zadrożny and Bartosz Trzaskowski
Pharmaceuticals 2021, 14(3), 179; https://doi.org/10.3390/ph14030179 - 24 Feb 2021
Cited by 4 | Viewed by 2291
Abstract
We have designed and synthesized a series of 60 new 5- and 7-hydroxycoumarin derivatives bearing the piperazine moiety with the expected binding to 5-HT1A and 5-HT2A receptors. Molecular docking of all investigated compounds revealed subnanomolar estimates of 5-HT1AR K [...] Read more.
We have designed and synthesized a series of 60 new 5- and 7-hydroxycoumarin derivatives bearing the piperazine moiety with the expected binding to 5-HT1A and 5-HT2A receptors. Molecular docking of all investigated compounds revealed subnanomolar estimates of 5-HT1AR Ki for three ligands and 5-HT2AR Ki for one ligand as well as numerous low nanomolar estimates of Ki for both receptors. Intrigued by these results we synthesized all 60 new derivatives using microwave-assisted protocols. We show that three new compounds show a relatively high antagonistic activity against the 5HT1A receptor, although lower than the reference compound WAY-100635. These compounds also showed relatively low binding affinities to the 5-HT2A receptor. We also provide a detailed structure–activity analysis of this series of compounds and compare it with previously obtained results for an exhaustive series of coumarin derivatives. Full article
(This article belongs to the Special Issue Molecular Pharmacology of 5-HT Receptors)
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Review

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17 pages, 15053 KiB  
Review
Serotonin 1A Receptor Pharmacotherapy and Neuroplasticity in Spinal Cord Injury
by Afaf Bajjig, Florence Cayetanot, J. Andrew Taylor, Laurence Bodineau and Isabelle Vivodtzev
Pharmaceuticals 2022, 15(4), 460; https://doi.org/10.3390/ph15040460 - 11 Apr 2022
Cited by 3 | Viewed by 3644
Abstract
Spinal cord injury is associated with damage in descending and ascending pathways between brainstem/cortex and spinal neurons, leading to loss in sensory-motor functions. This leads not only to locomotor reduction but also to important respiratory impairments, both reducing cardiorespiratory engagement, and increasing cardiovascular [...] Read more.
Spinal cord injury is associated with damage in descending and ascending pathways between brainstem/cortex and spinal neurons, leading to loss in sensory-motor functions. This leads not only to locomotor reduction but also to important respiratory impairments, both reducing cardiorespiratory engagement, and increasing cardiovascular risk and mortality. Moreover, individuals with high-level injuries suffer from sleep-disordered breathing in a greater proportion than the general population. Although no current treatments exist to restore motor function in spinal cord injury (SCI), serotoninergic (5-HT) 1A receptor agonists appear as pharmacologic neuromodulators that could be important players in inducing functional improvements by increasing the activation of spared motoneurons. Indeed, single therapies of serotoninergic 1A (5-HT1A) agonists allow for acute and temporary recovery of locomotor function. Moreover, the 5-HT1A agonist could be even more promising when combined with other pharmacotherapies, exercise training, and/or spinal stimulation, rather than administered alone. In this review, we discuss previous and emerging evidence showing the value of the 5HT1A receptor agonist therapies for motor and respiratory limitations in SCI. Moreover, we provide mechanistic hypotheses and clinical impact for the potential benefit of 5-HT1A agonist pharmacology in inducing neuroplasticity and improving locomotor and respiratory functions in SCI. Full article
(This article belongs to the Special Issue Molecular Pharmacology of 5-HT Receptors)
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46 pages, 6710 KiB  
Review
Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence
by Gustavo R. Villas-Boas, Stefânia N. Lavorato, Marina M. Paes, Pablinny M. G. de Carvalho, Vanessa C. Rescia, Mila S. Cunha, Manoel F. de Magalhães-Filho, Luis F. Ponsoni, Adryano Augustto Valladao de Carvalho, Roseli B. de Lacerda, Lais da S. Leite, Matheus da S. Tavares-Henriques, Luiz A. F. Lopes, Luiz G. R. Oliveira, Saulo E. Silva-Filho, Ana P. S. da Silveira, Roberto K. N. Cuman, Francielli M. de S. Silva-Comar, Jurandir F. Comar, Luana do A. Brasileiro, Jussileide N. dos Santos, William R. de Freitas, Katyuscya V. Leão, Jonatas G. da Silva, Raphael C. Klein, Mary H. F. Klein, Bruno H. da S. Ramos, Cristiane K. C. Fernandes, Dayane G. de L. Ribas and Silvia A. Oesterreichadd Show full author list remove Hide full author list
Pharmaceuticals 2021, 14(2), 148; https://doi.org/10.3390/ph14020148 - 12 Feb 2021
Cited by 21 | Viewed by 6750
Abstract
Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such [...] Read more.
Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the “serotonergic receptosome” in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors. Full article
(This article belongs to the Special Issue Molecular Pharmacology of 5-HT Receptors)
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30 pages, 11224 KiB  
Review
Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor
by Qing Wang, Yu Zhou, Jianhui Huang and Niu Huang
Pharmaceuticals 2021, 14(2), 76; https://doi.org/10.3390/ph14020076 - 20 Jan 2021
Cited by 10 | Viewed by 4578
Abstract
Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has [...] Read more.
Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas. Full article
(This article belongs to the Special Issue Molecular Pharmacology of 5-HT Receptors)
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