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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 -
Supportive Care in Cancer : Official... Mar 2019Radiation-induced nausea and vomiting (RINV) can affect 50-80% of patients undergoing radiotherapy and negatively impacts quality of life. This review aimed to compare... (Comparative Study)
Comparative Study Review
PURPOSE
Radiation-induced nausea and vomiting (RINV) can affect 50-80% of patients undergoing radiotherapy and negatively impacts quality of life. This review aimed to compare the most recent RINV antiemetic guidelines produced by the Multinational Association for Supportive Care in Cancer (MASCC), the European Society of Clinical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN). Future improvements to the guidelines and the need for further research in RINV were also discussed.
METHODS
Antiemetic guidelines produced by MASCC/ESMO, ASCO, and NCCN were examined to identify similarities, differences, and inadequacies within the guidelines.
RESULTS
Areas of dissension within the guidelines include the addition of dexamethasone to moderate-risk antiemetic regimens, the prophylactic treatment of RINV in the low-risk categories, and the appropriate treatment for breakthrough emesis. The guidelines are in accordance that high-risk radiotherapy regimens should be treated prophylactically with a serotonin receptor antagonist and for those undergoing concurrent chemotherapy and radiotherapy, antiemetic treatment should be prescribed according to the emetic risk associated with their respective chemotherapy regimen. Low- and minimal-risk recommendations are based on low-level evidence and informal consensus.
CONCLUSION
RINV is a frequent and distressing side effect of radiotherapy and requires further research to establish effective antiemetic guidelines and ensure optimal treatment outcomes.
Topics: Antiemetics; Consensus; Dexamethasone; Emetics; Humans; Nausea; Neoplasms; Practice Guidelines as Topic; Quality of Life; Radiotherapy; Research; Risk Factors; Serotonin Antagonists; Vomiting
PubMed: 30607675
DOI: 10.1007/s00520-018-4586-2 -
Sexual Medicine Reviews Oct 2019Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired,... (Review)
Review
INTRODUCTION
Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss.
AIM
To understand possible mechanisms by which flibanserin may produce weight loss.
METHODS
A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management.
MAIN OUTCOME MEASURES
Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss.
RESULTS
Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT receptors and factors such as improved mood and improved sleep.
CONCLUSION
Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586.
Topics: Arousal; Benzimidazoles; Energy Intake; Female; Humans; Libido; Serotonin Antagonists; Serotonin Receptor Agonists; Sexual Dysfunctions, Psychological; Weight Loss
PubMed: 31196764
DOI: 10.1016/j.sxmr.2019.04.003 -
Expert Opinion on Investigational Drugs Jun 2018Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist... (Review)
Review
INTRODUCTION
Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile.
AREAS COVERED
5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD.
EXPERT OPINION
Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.
Topics: Alzheimer Disease; Animals; Benzylamines; Cholinesterase Inhibitors; Cognition; Drug Design; Humans; Indoles; Piperazines; Quinolines; Receptors, Serotonin; Serotonin Antagonists; Sulfones
PubMed: 29848076
DOI: 10.1080/13543784.2018.1483334 -
Journal of Biochemical and Molecular... Sep 2019This study was performed to investigate the effect of ondansetron, a serotonin receptor (5-HT3) antagonist, in the alleviation of diclofenac-induced kidney injuries....
This study was performed to investigate the effect of ondansetron, a serotonin receptor (5-HT3) antagonist, in the alleviation of diclofenac-induced kidney injuries. NMRI mice were randomly divided into six groups and treated with (A) untreated control group, (B) diclofenac (100 mg/kg), (C) ondansetron (1 mg/kg), (D to F) ondansetron (0.1, 0.5, and 1 mg/kg, respectively) and diclofenac (100 mg/kg) for last 3 days of experiment. The oxidative stress tests strongly demonstrated the negative synergistic effects of diclofenac and ondansetron, regarding the observation of dose-dependent enhancement of malondialdehyde concentration, and reduction of glutathione content, and superoxide dismutase and catalase activity. Histopathological analyses revealed dose-dependent tubular epithelial cells degeneration, outstanding mononuclear cells infiltration, clear necrosis at the papillary region of kidney, dilation, and vascular hyperemia in mice kidney tissues treated with ondansetron and diclofenac. Conclusively, these findings suggested the possible ondansetron-diclofenac interaction through the induction of oxidative stress.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Catalase; Diclofenac; Dose-Response Relationship, Drug; Drug Synergism; Glutathione; Kidney; Mice; Ondansetron; Serotonin Antagonists; Superoxide Dismutase
PubMed: 31332906
DOI: 10.1002/jbt.22378 -
Annals of Palliative Medicine Apr 2018Chemotherapy-induced nausea and vomiting (CINV), a common side effect of chemotherapy, can substantially impair a patient's quality of life, interfere with a patient's... (Comparative Study)
Comparative Study Review
Efficacy of the combination neurokinin-1 receptor antagonist, palonosetron, and dexamethasone compared to others for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Chemotherapy-induced nausea and vomiting (CINV), a common side effect of chemotherapy, can substantially impair a patient's quality of life, interfere with a patient's compliance with anticancer therapy, and result in the manifestation of adverse events such as electrolyte imbalance, dehydration and malnutrition. The most recent guidelines published by the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) recommend the combination of dexamethasone (DEX), a 5-hydroxytrypatmine-3 receptor antagonist (5-HT3RA), preferably palonosetron (PALO), and a neurokinin-1 receptor antagonist (NK1RA) for prophylactic treatment of CINV in patients receiving highly emetogenic chemotherapy (HEC). The aim of this review was to examine the efficacy of triple agent, as reported in randomized controlled trials (RCTs), compared to any other prophylactic treatments.
METHODS
A literature search was conducted in Ovid MEDLINE(R), Embase Classic & Embase, and the Cochrane Central Register of Controlled Trials. The primary endpoint was the proportion of patients achieving complete response (CR) in the acute, delayed and overall phase. Secondary endpoints included the percentage of patients who achieved complete control (CC), no nausea and no vomiting in the acute, delayed and overall phases.
RESULTS
A total of 17 RCTs were included in this review, of which 3,146 patients were randomized to receive NK1RA, PALO and DEX, and 2,987 patients to receive other antiemetic treatments. The combination was not superior to other treatments in five endpoints-CC and CR in the acute phase, nausea and emesis control in the delayed phase, and nausea in the overall phase-but was superior in the other 11 endpoints. When looking only at HEC and moderately emetogenic chemotherapy (MEC) studies, the combination was only superior to others in three endpoints (delayed and overall CC, and overall emesis control) in HEC setting, which is less than the nine identified endpoints (delayed and overall CR, delayed and overall CC, acute and overall nausea control, and acute, delayed and overall phases for emesis control) in the MEC setting.
CONCLUSIONS
The combination of NK1RA, PALO and DEX is superior in the majority of assessed endpoints of this meta-analysis. Further studies should investigate the efficacy and safety of the triple regimen compared to regimens lacking NK1RA, to add to the discussions about whether future CINV prophylaxis guidelines should include NK1RA as a first-line treatment in the MEC setting.
Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Dexamethasone; Drug Combinations; Female; Humans; Isoquinolines; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Palonosetron; Quinuclidines; Radiotherapy; Randomized Controlled Trials as Topic; Serotonin Antagonists; Vomiting
PubMed: 29764184
DOI: 10.21037/apm.2018.03.09 -
The Journal of Pharmacology and... Jul 2021TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine...
TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine receptors that is currently in clinical trial for the treatment of psychiatric disorders. In vitro binding study showed that TPN672 exhibited extremely high affinity for serotonin 1A receptor (5-HTR) ( = 0.23 nM) and 5-HTR ( = 2.58 nM) as well as moderate affinity for DR ( = 11.55 nM) and DR ( = 17.91 nM). In vitro functional assays demonstrated that TPN672 acted as a potent 5-HTR agonist, DR/DR partial agonist, and 5-HTR antagonist. TPN672 displayed robust antipsychotic efficacy in rodent models (e.g., blocking phencyclidine-induced hyperactivity), significantly better than aripiprazole, and ameliorated negative symptoms and cognitive deficits in the sociability test, dark avoidance response, Morris water maze test, and novel object recognition test. The results of electrophysiological experiments showed that TPN672 might inhibit the excitability of the glutamate system through activating 5-HTR in medial prefrontal cortex, thereby improving cognitive and negative symptoms. Moreover, the safety margin (the ratio of minimum catalepsy-inducing dose to minimum effective dose) of TPN672 was about 10-fold, which was superior to aripiprazole. In conclusion, TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having lower risk of extrapyramidal symptoms and hyperprolactinemia. SIGNIFICANCE STATEMENT: TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having a lower risk of extrapyramidal symptoms and hyperprolactinemia. A phase I clinical trial is now under way to test its tolerance, pharmacokinetics, and pharmacodynamic effects in human volunteers. Accordingly, the present results will have significant impact on the development of new antischizophrenia drugs.
Topics: Animals; Antipsychotic Agents; Avoidance Learning; Female; HEK293 Cells; Humans; Male; Mice; Mice, Inbred ICR; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Serotonin Receptor Agonists; Treatment Outcome
PubMed: 33975897
DOI: 10.1124/jpet.120.000414 -
CNS Spectrums Feb 2015Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual... (Review)
Review
Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire.
Topics: Benzimidazoles; Brain; Female; Humans; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Sexual Dysfunctions, Psychological
PubMed: 25659981
DOI: 10.1017/S1092852914000832 -
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 -
Pharmacological Reports : PR Jun 2020LY393558 is a combined antagonist of serotonin (5-HT) 5-HT receptors and inhibitor of serotonin transporter (SERT). LY393558 reduces 5-HT-induced vasoconstriction and...
Reduction of the serotonin 5-HT and 5-HT receptor-mediated contraction of human pulmonary artery by the combined 5-HT receptor antagonist and serotonin transporter inhibitor LY393558.
BACKGROUND
LY393558 is a combined antagonist of serotonin (5-HT) 5-HT receptors and inhibitor of serotonin transporter (SERT). LY393558 reduces 5-HT-induced vasoconstriction and remodelling of rat and/or mouse pulmonary arteries. The aim of our study was to examine the effect of LY393558 on the 5-HT-stimulated vasoconstriction of human pulmonary arteries (hPAs) and to determine the underlying mechanism(s).
METHODS
Vascular effects of 5-HT receptor agonists, antagonists and a SERT inhibitor were examined in organ bath studies on intralobar hPAs obtained from patients during resection of lung carcinoma.
RESULTS
Serotonin and agonists of the 5-HT receptor (5-carboxamidotryptamine, 5-CT) and 5-HT receptor (α-methyl-5-HT) contracted endothelium-intact hPAs in a concentration-dependent fashion. The 5-HT antagonists SB224289 and GR55562 reduced responses induced by 5-HT and 5-CT and the 5-HT antagonist ketanserin inhibited the effects of 5-HT and α-methyl-5-HT. Administration of the SERT inhibitor citalopram (at a concentration that failed to modify the 5-HT-induced vasoconstriction) in combination with SB224289 or GR55562 was more effective in inhibiting the response to 5-HT than the 5-HT antagonists alone. LY393558 showed the greatest antagonistic effect against the vasoconstriction elicited by 5-HT, 5-CT and α-methyl-5-HT.
CONCLUSIONS
LY393558 reduces the 5-HT-induced contraction antagonizing 5-HT and 5-HT receptors probably due to synergic interaction between SERT inhibition and 5-HT receptor antagonism. Thus, it might represent a valuable future option in the pulmonary arterial hypertension therapy.
Topics: Aged; Benzamides; Citalopram; Cyclic S-Oxides; Female; Humans; Male; Middle Aged; Piperidones; Pulmonary Artery; Pyridines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Selective Serotonin Reuptake Inhibitors; Spiro Compounds; Thiadiazines; Vasoconstriction
PubMed: 32333296
DOI: 10.1007/s43440-020-00105-2