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Recent Developments in Serotonin Receptors Research

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 35292

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Dr. Marcello Leopoldo

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Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari, Bari, Italy
Interests: medicinal chemistry; serotonin receptors; dopamine receptors; formyl peptide receptors; positron emission tomography; fluorescent ligands
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Dr. Enza Lacivita

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Dear Colleagues,

Serotonin (5-HT) receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiological and pathophysiological processes. Selective agonists and antagonists for 5-HT receptor subtypes as well as compounds acting at multiple 5-HT receptors have been developed, and therapeutic utility is being pursued. In this Special Issue, we intend to provide the reader with the recent developments in serotonin research. Thus, the submissions of papers describing new molecules showing activity through one or more 5-HT receptors are welcome. In addition, manuscripts describing new 5-HT receptor-based chemical tools or approaches for the study of 5-HT function, prospective analysis for the therapeutic future of 5-HT ligands, and reviews will also be taken into consideration. Finally, authors are encouraged to propose topics that will be evaluated accordingly. Overall, we hope that this time-focused issue summarizing our current knowledge on 5-HT receptors ligands will be of interest to a wide range of readers of the journal.

Dr. Marcello Leopoldo
Dr. Enza Lacivita
Guest Editors

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Keywords

Medicinal chemistry
Serotonin receptor ligands
Therapeutics
G protein-coupled receptors
Agonist
Antagonist
Biased ligands
Fluorescent ligands

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Published Papers (9 papers)

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16 pages, 4260 KiB

Open AccessArticle

Design and Synthesis of Arylpiperazine Serotonergic/Dopaminergic Ligands with Neuroprotective Properties

by Margherita Mastromarino, Mauro Niso, Carmen Abate, Ewgenij Proschak, Mariam Dubiel, Holger Stark, Marián Castro, Enza Lacivita and Marcello Leopoldo

Molecules 2022, 27(4), 1297; https://doi.org/10.3390/molecules27041297 - 15 Feb 2022

Cited by 3 | Viewed by 2650

Abstract

Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT_1A, 5-HT_2A, 5-HT₇ receptor, and dopamine D₂ receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis. All the new compounds showed CNS MultiParameter Optimization score predictive of desirable ADMET properties and cross the blood–brain barrier. We identified compound 12a that combines an affinity profile compatible with antipsychotic activity (5-HT_1AK_i = 41.5 nM, 5-HT_2AK_i = 315 nM, 5-HT₇K_i = 42.5 nM, D₂K_i = 300 nM), and compound 9b that has an affinity profile consistent with studies in the context of ASD (5-HT_1AK_i = 23.9 nM, 5-HT_2AK_i = 39.4 nM, 5-HT₇K_i = 45.0 nM). Both compounds also had antioxidant properties. All compounds showed low in vitro metabolic stability, the only exception being compound 9b, which might be suitable for studies in vivo. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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17 pages, 1858 KiB

Open AccessArticle

Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson’s Disease

by Feras Altwal, Fernando E. Padovan-Neto, Alexandra Ritger, Heinz Steiner and Anthony R. West

Molecules 2021, 26(19), 5790; https://doi.org/10.3390/molecules26195790 - 24 Sep 2021

Cited by 11 | Viewed by 2887

Abstract

L-DOPA therapy in Parkinson’s disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr_1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr_1A antagonist WAY-100635, demonstrating a critical role for 5-HTr_1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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18 pages, 23603 KiB

Open AccessArticle

N-Skatyltryptamines—Dual 5-HT₆R/D₂R Ligands with Antipsychotic and Procognitive Potential

by Agata Hogendorf, Adam S. Hogendorf, Rafał Kurczab, Grzegorz Satała, Bernadeta Szewczyk, Paulina Cieślik, Gniewomir Latacz, Jadwiga Handzlik, Tomasz Lenda, Katarzyna Kaczorowska, Jakub Staroń, Ryszard Bugno, Beata Duszyńska and Andrzej J. Bojarski

Molecules 2021, 26(15), 4605; https://doi.org/10.3390/molecules26154605 - 29 Jul 2021

Cited by 3 | Viewed by 2576

Abstract

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT_1A, 5-HT_2A, 5-HT₆, and D₂ receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D₂ receptor antagonists with additional 5-HT₆R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT₆R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT₆R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D₂R antagonist function combined with 5-HT₆R agonism, and mixed D₂/5-HT₆R antagonists in murine models of psychosis. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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17 pages, 3493 KiB

Open AccessArticle

Environment-Sensitive Fluorescence of 7-Nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-Labeled Ligands for Serotonin Receptors

by Parijat Sarkar, Kaleeckal G. Harikumar, Satinder S. Rawat, Sanjib Das, Tushar K. Chakraborty and Amitabha Chattopadhyay

Molecules 2021, 26(13), 3848; https://doi.org/10.3390/molecules26133848 - 24 Jun 2021

Cited by 8 | Viewed by 3519

Abstract

Serotonin is a neurotransmitter that plays a crucial role in the regulation of several behavioral and cognitive functions by binding to a number of different serotonin receptors present on the cell surface. We report here the synthesis and characterization of several novel fluorescent analogs of serotonin in which the fluorescent NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) group is covalently attached to serotonin. The fluorescent ligands compete with the serotonin_1A receptor specific radiolabeled agonist for binding to the receptor. Interestingly, these fluorescent ligands display a high environmental sensitivity of their fluorescence. Importantly, the human serotonin_1A receptor stably expressed in CHO-K1 cells could be specifically labeled with one of the fluorescent ligands with minimal nonspecific labeling. Interestingly, we show by spectral imaging that the NBD-labeled ligand exhibits a red edge excitation shift (REES) of 29 nm when bound to the receptor, implying that it is localized in a restricted microenvironment. Taken together, our results show that NBD-labeled serotonin analogs offer an attractive fluorescent approach for elucidating the molecular environment of the serotonin binding site in serotonin receptors. In view of the multiple roles played by the serotonergic systems in the central and peripheral nervous systems, these fluorescent ligands would be useful in future studies involving serotonin receptors. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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19 pages, 2518 KiB

Open AccessArticle

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties

by Vittorio Canale, Magdalena Kotańska, Anna Dziubina, Matylda Stefaniak, Agata Siwek, Gabriela Starowicz, Krzysztof Marciniec, Patryk Kasza, Grzegorz Satała, Beata Duszyńska, Xavier Bantreil, Frédéric Lamaty, Marek Bednarski, Jacek Sapa and Paweł Zajdel

Molecules 2021, 26(13), 3828; https://doi.org/10.3390/molecules26133828 - 23 Jun 2021

Cited by 11 | Viewed by 3346

Abstract

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α₂-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT₇ receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α₂-adrenoceptors and 5-HT₇ receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α_2A/5-HT₇ receptor antagonist and displayed moderate-to-high selectivity over α₁-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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18 pages, 2048 KiB

Open AccessArticle

Cardamonin Modulates Neuropathic Pain through the Possible Involvement of Serotonergic 5-HT1A Receptor Pathway in CCI-Induced Neuropathic Pain Mice Model

by Nur Khalisah Kaswan, Noor Aishah Binti Mohammed Izham, Tengku Azam Shah Tengku Mohamad, Mohd Roslan Sulaiman and Enoch Kumar Perimal

Molecules 2021, 26(12), 3677; https://doi.org/10.3390/molecules26123677 - 16 Jun 2021

Cited by 13 | Viewed by 4253

Abstract

Cardamonin, a naturally occurring chalcone isolated from Alpinia species has shown to possess strong anti-inflammatory and anti-nociceptive activities. Previous studies have demonstrated that cardamonin exerts antihyperalgesic and antiallodynic properties in chronic constriction injury (CCI)-induced neuropathic pain animal model. However, the mechanisms underlying cardamonin’s effect have yet to be fully understood. The present study aims to investigate the involvement of the serotonergic system in cardamonin induced antihyperalgesic and antiallodynic effects in CCI-induced neuropathic pain mice model. The neuropathic pain symptoms in the CCI mice model were assessed using Hargreaves Plantar test and von-Frey filament test on day 14 post-surgery. Central depletion of serotonin along the descending serotonergic pathway was done using ρ-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis for four consecutive days before cardamonin treatment, and was found to reverse the antihyperalgesic and antiallodynic effect produced by cardamonin. Pretreatment of the mice with several 5-HT receptor subtypes antagonists: methiothepin (5-HT1/6/7₇ receptor antagonist, 0.1 mg/kg), WAY 100635 (5-HT1A receptor antagonist, 1 mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5 mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3 mg/kg), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg) were shown to abolish the effect of cardamonin induced antihyperalgesic and antiallodynic effects. Further evaluation of the 5-HT1A receptor subtype protein expressions reveals that cardamonin significantly upregulated its expression in the brainstem and spinal cord. Our results suggest that the serotonergic pathway is essential for cardamonin to exert its antineuropathic effect in CCI mice through the involvement of the 5-HT1A receptor subtype in the central nervous system. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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14 pages, 3319 KiB

Open AccessArticle

Differential Regulation of Human Serotonin Receptor Type 3A by Chanoclavine and Ergonovine

by Sanung Eom, Woog Jung, Jaeeun Lee, Hye Duck Yeom, Shinhui Lee, Chaelin Kim, Heui-Dong Park and Junho H. Lee

Molecules 2021, 26(5), 1211; https://doi.org/10.3390/molecules26051211 - 24 Feb 2021

Cited by 6 | Viewed by 2588

Abstract

Irritable bowel syndrome (IBS) is a chronic disease that causes abdominal pain and an imbalance of defecation patterns due to gastrointestinal dysfunction. The cause of IBS remains unclear, but intestinal-brain axis problems and neurotransmitters have been suggested as factors. In this study, chanoclavine, which has a ring structure similar to 5-hydroxytryptamine (5-HT), showed an interaction with the 5-HT_3A receptor to regulate IBS. Although its derivatives are known to be involved in neurotransmitter receptors, the molecular physiological mechanism of the interaction between chanoclavine and the 5-HT_3A receptor is unknown. Electrophysiological experiments were conducted using a two-electrode voltage-clamp analysis to observe the inhibitory effects of chanoclavine on Xenopus oocytes in which the h5-HT_3A receptor was expressed. The co-application of chanoclavine and 5-HT resulted in concentration-dependent, reversible, voltage-independent, and competitive inhibition. The 5-HT_3A response induced by 5-HT was blocked by chanoclavine with half-maximal inhibitory response concentration (IC₅₀) values of 107.2 µM. Docking studies suggested that chanoclavine was positioned close F130 and N138 in the 5-HT_3A receptor-binding site. The double mutation of F130A and N138A significantly attenuated the interaction of chanoclavine compared to a single mutation or the wild type. These data suggest that F130 and N138 are important sites for ligand binding and activity. Chanoclavine and ergonovine have different effects. Asparagine, the 130th amino acid sequence of the 5-HT_3A receptor, and phenylalanine, the 138th, are important in the role of binding chanoclavine, but ergonovine has no interaction with any amino acid sequence of the 5-HT_3A receptor. The results of the electrophysiological studies and of in silico simulation showed that chanoclavine has the potential to inhibit the hypergastric stimulation of the gut by inhibiting the stimulation of signal transduction through 5-HT_3A receptor stimulation. These findings suggest chanoclavine as a potential antiemetic agent for excessive gut stimulation and offer insight into the mechanisms of 5-HT_3A receptor inhibition. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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Review

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16 pages, 2304 KiB

Open AccessReview

Modulation of Serotonin Receptors in Neurodevelopmental Disorders: Focus on 5-HT7 Receptor

by Jieon Lee, Diana Avramets, Byungsun Jeon and Hyunah Choo

Molecules 2021, 26(11), 3348; https://doi.org/10.3390/molecules26113348 - 2 Jun 2021

Cited by 25 | Viewed by 7846

Abstract

Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and develop treatments. Although there are drugs such as aripiprazole, risperidone, and lurasidone, these medications are not cures for the disorders and can only help people feel better or alleviate their symptoms. Thus, it is required to discover therapeutic targets in order to find the ultimate treatments of neurodevelopmental disorders. It is suggested that abnormal neuronal morphology in the neurodevelopment process is a main cause of NDDs, in which the serotonergic system is emerging as playing a crucial role. From this point of view, we noticed the correlation between serotonin receptor subtype 7 (5-HT₇R) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HT₇R modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HT₇R/G₁₂ signaling pathway. Through the investigation of recent studies, it is suggested that 5-HT₇R could be a potential therapeutic target for the treatment of NDDs. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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16 pages, 1068 KiB

Open AccessReview

The Role of Serotonin in Breast Cancer Stem Cells

by William D. Gwynne, Mirza S. Shakeel, Adele Girgis-Gabardo and John A. Hassell

Molecules 2021, 26(11), 3171; https://doi.org/10.3390/molecules26113171 - 26 May 2021

Cited by 12 | Viewed by 4365

Abstract

Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer. Full article

(This article belongs to the Special Issue Recent Developments in Serotonin Receptors Research)

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