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Biomolecules Feb 2023Serotonin (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... (Review)
Review
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-HT) receptor has been an area of substantial research. 5-HT 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-HT receptor antagonists. Several 5-HT 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-HT receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT 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-HT receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.
Topics: Animals; Serotonin; Alzheimer Disease; Receptors, Serotonin; Serotonin Antagonists
PubMed: 36830678
DOI: 10.3390/biom13020309 -
Pharmacology & Therapeutics May 1995Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on... (Review)
Review
Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on operational criteria (agonist and antagonist rank order), as well as transduction mechanisms involved and the structure of the receptor protein, the Nomenclature Committee of the Serotonin Club has proposed the following classification and nomenclature: the main receptor types 5-HT1 to 5-HT4, recombinant receptors (e.g. 5-ht5 to 5-ht7) and 'orphan' receptors. The aim of the present review is to discuss the events leading to this classification, the criteria for and functional responses mediated by various 5-HT receptors, as well as the therapeutic possibilities with 5-HT ligands.
Topics: Animals; Anxiety Disorders; Depressive Disorder; Humans; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 7667401
DOI: 10.1016/0163-7258(94)00005-n -
Identification and Pharmacological Characterization of Two Serotonin Type 7 Receptor Isoforms from .International Journal of Molecular... Dec 2022Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive molecule, as neurotransmitters regulate various biological functions in vertebrates and invertebrates...
Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive molecule, as neurotransmitters regulate various biological functions in vertebrates and invertebrates by binding and activating specific 5-HT receptors. The pharmacology and tissue distribution of 5-HT receptors have been investigated in several model insects, and these receptors are recognized as potential insecticide targets. However, little is known about the pharmacological characterization of the 5-HT receptors in important agricultural pests. In this study, we investigated the sequence, pharmacology, and tissue distribution of receptors from oriental armyworm (Walker) (Lepidoptera: Noctuidae), an important migratory and polyphagous pest species. We found that the receptor gene encodes two molecularly distinct transcripts, and , by the mechanism of alternative splicing in . Msep5-HT7S differs from Msep5-HT7L based on the deletion of 95 amino acids within the third intracellular loop. Two Msep5-HT7 receptor isoforms were activated by 5-HT and synthetic agonists α-methylserotonin, 8-hydroxy-DPAT, and 5-methoxytryptamine, resulting in increased intracellular cAMP levels in a dose-dependent manner, although these agonists showed much poorer potency and efficacy than 5-HT. The maximum efficacy of 5-HT compared to the two 5-HT isoforms was equivalent, but 5-HT exhibited 2.63-fold higher potency against the Msep5-HT7S than the Msep5-HT7L receptor. These two isoforms were also blocked by the non-selective antagonist methiothepin and the selective antagonists WAY-100635, ketanserin, SB-258719, and SB-269970. Moreover, two distinct mRNA transcripts were expressed preferentially in the brain and chemosensory organs of adults, as determined by qPCR assay. This study is the first comprehensive characterization of two splicing isoforms of 5-HT7 receptors in , and the first to demonstrate that alternative splicing is also the mechanism for producing multiple 5-HT7 isoforms in insects. Pharmacological and gene expression profiles offer important information that could facilitate further exploration of their function in the central nervous system and peripheral chemosensory organs, and may even contribute to the development of new selective pesticides.
Topics: Animals; Serotonin; Serotonin Antagonists; Receptors, Serotonin; Moths; Protein Isoforms
PubMed: 36614100
DOI: 10.3390/ijms24010655 -
Biological & Pharmaceutical Bulletin Jun 2022Nutmeg, a dried seed kernel of a tall evergreen Myristicaceae tree, is widely used as a spice and herbal medicine and is known to have antidepressant-like effects. This...
Nutmeg, a dried seed kernel of a tall evergreen Myristicaceae tree, is widely used as a spice and herbal medicine and is known to have antidepressant-like effects. This study evaluates the mechanisms underlying this antidepressant-like effect and safety of nutmeg n-hexane extract (NNE) in mice. Tail suspension and open field tests showed that NNE (10 mg/kg, per OS (p.o.)) significantly decreased the immobility time of mice without effecting their spontaneous locomotor activity. The reduction of immobility time of mice elicited by NNE was significantly inhibited by ketanserin (5-hydroxytryptamine (5-HT) receptor antagonist), ondansetron (5-HT receptor antagonist), and yohimbine (α receptor antagonist). WAY100635 (5-HT receptor antagonist) tended to inhibit the effect of NNE but without significance. Testing according to the Organisation for Economic Co-operation and Development Guidelines, no mice died due to administrated NNE (2000 mg/kg, p.o.), and behavioral and weight changes were not seen in the acute toxicity test. In the Ames test, no increase in the number of revertant colonies for each bacterial strain test strains TA98 and TA100 by nutmeg powder was observed either with or without metabolic activity by S9 mix. These results suggest that NNE shows an antidepressant-like effect involving various serotonergic and noradrenergic nervous systems and maybe a highly safe natural preparation.
Topics: Animals; Antidepressive Agents; Depression; Hindlimb Suspension; Mice; Myristica; Serotonin; Serotonin Antagonists; Swimming
PubMed: 35314522
DOI: 10.1248/bpb.b21-01059 -
Epilepsia Dec 2009Experimental studies suggest that 5-hydroxytryptamine (5-HT) receptors play a role in epileptogenesis and seizure propagation. Ondansetron, a 5-HT(3) receptor... (Comparative Study)
Comparative Study
Experimental studies suggest that 5-hydroxytryptamine (5-HT) receptors play a role in epileptogenesis and seizure propagation. Ondansetron, a 5-HT(3) receptor antagonist, has been reported to have proconvulsant and anticonvulsant effects in animals. We describe three patients who developed seizures after receiving ondansetron. There were two females and one male. Ages ranged from 38-56 years. None had a previous or family history of seizures. Four milligrams (mg) of ondansetron was given intravenously for severe nausea and vomiting in association with migraine, gastritis, and diabetic ketoacidosis. A generalized tonic-clonic seizure occurred in each patient--12, 15, and 22 min after injection. Brain magnetic resonance imaging (MRI) and electroencephalography (EEG) were normal in all patients. Although no antiepileptic drugs were given, none had seizure recurrence subsequently. The temporal relationship between ondansetron administration and seizures, lack of EEG or MRI abnormalities, and absence of seizure recurrence suggest that the seizures were causally related to ondansetron in our patients.
Topics: Adult; Electroencephalography; Epilepsy; Epilepsy, Tonic-Clonic; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Migraine Disorders; Nausea; Ondansetron; Receptors, Serotonin; Recurrence; Seizures; Serotonin; Serotonin Antagonists; Vomiting
PubMed: 19490041
DOI: 10.1111/j.1528-1167.2009.02139.x -
Current Neuropharmacology 2023The biogenic amine serotonin modulates pain perception by activating several types of serotonergic receptors, including the 5-HT type. These receptors are widely... (Review)
Review
The biogenic amine serotonin modulates pain perception by activating several types of serotonergic receptors, including the 5-HT type. These receptors are widely expressed along the pain axis, both peripherally, on primary nociceptors, and centrally, in the spinal cord and the brain. The role of 5-HT receptors in modulating pain has been explored in vivo in different models of inflammatory and neuropathic pain. While most studies have reported an antinociceptive effect of 5-HT receptor activation, some authors have suggested a pronociceptive action. Differences in pain models, animal species and gender, receptor types, agonists, and route of administration could explain these discrepancies. In this mini-review, some of the main findings concerning the function of 5-HT receptors in the pain system have been presented. The expression patterns of the receptors at the different levels of the pain axis, along with the cellular mechanisms involved in their activity, have been described. Alterations in receptor expression and/or function in different pain models and the role of 5-HT receptors in controlling pain transmission have also been discussed. Finally, some of the future perspectives in this field have been outlined.
Topics: Animals; Serotonin; Serotonin Antagonists; Receptors, Serotonin; Nociception; Neuralgia; Spinal Cord
PubMed: 36453491
DOI: 10.2174/1570159X21666221129101800 -
Nature Structural & Molecular Biology Jul 2022Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell...
Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.
Topics: Humans; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 35835867
DOI: 10.1038/s41594-022-00796-6 -
The American Journal of Case Reports May 2018BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone....
BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.
Topics: Benzodiazepines; Bupropion; Cyproheptadine; Dopamine Uptake Inhibitors; Drug Overdose; Fluoxetine; Humans; Male; Olanzapine; Risperidone; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Serotonin Syndrome; Selective Serotonin Reuptake Inhibitors; Time Factors; Trazodone; Young Adult
PubMed: 29795058
DOI: 10.12659/AJCR.909063 -
Molecules (Basel, Switzerland) Jun 2021Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and... (Review)
Review
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-HTR) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HTR modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HTR/G signaling pathway. Through the investigation of recent studies, it is suggested that 5-HTR could be a potential therapeutic target for the treatment of NDDs.
Topics: Animals; Humans; Molecular Targeted Therapy; Neurodevelopmental Disorders; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction
PubMed: 34199418
DOI: 10.3390/molecules26113348 -
Current Topics in Medicinal Chemistry 2010Arylsulfonyl analogs of aminopyrimidines (e.g. Ro 04-6790; 2), aminopyridines (e.g. Ro 63-0563; 3), 1-phenylpiperazines (e.g. SB-271046; 4), and tryptamines (e.g.... (Review)
Review
Arylsulfonyl analogs of aminopyrimidines (e.g. Ro 04-6790; 2), aminopyridines (e.g. Ro 63-0563; 3), 1-phenylpiperazines (e.g. SB-271046; 4), and tryptamines (e.g. MS-245; 5) were described as the first examples of selective 5-HT(6) receptor antagonists only ten years ago. Today, hundreds of compounds of seemingly diverse structure have been reported. The early antagonists featured an arylsulfonyl group leading to the wide notspread assumption that an arylsulfonyl moiety might be critical for binding and antagonist action. With respect to the arylsulfonyltryptamines, it seems that neither the "arylsulfonyl" nor the "tryptamine" portion of these compounds is essential for binding or for antagonist action, and some such derivatives even display agonist action. The present review describes many of the currently available 5-HT(6) receptor ligands and, unlike prior reviews, provides a narrative of the thinking (where possible) that led to their design, synthesis, and evaluation. The arylsulfonyltryptamines are also used as the structural basis of attempts to relate various structure-types to one another to afford a better understanding of the overall structural requirements for 5-HT(6) receptor binding.
Topics: Chemistry, Pharmaceutical; Ligands; Receptors, Serotonin; Serotonin Antagonists; Structure-Activity Relationship; Tryptamines
PubMed: 20166945
DOI: 10.2174/156802610791111542