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Best Practice & Research. Clinical... Dec 2020Antiemetic prophylaxis for postoperative nausea and vomiting (PONV) - a frequent complication in the postoperative period - is routinely given to high-risk patients.... (Review)
Review
Antiemetic prophylaxis for postoperative nausea and vomiting (PONV) - a frequent complication in the postoperative period - is routinely given to high-risk patients. However, standard PONV risk models do not account for genetic factors, which have been shown to have a significant influence on PONV incidence and drug response. In this review, we describe the polymorphisms of various genes (serotonin, dopamine, cholinergic, etc.) and how pharmacogenomics is involved in the pathophysiology of PONV. This review also addresses how genetics is involved in today's clinical practice related to PONV and how it will change in the upcoming years as personalized medicine advances.
Topics: Antiemetics; Disease Management; Genetic Testing; Humans; Pharmacogenetics; Postoperative Nausea and Vomiting; Receptors, Dopamine; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists
PubMed: 33288121
DOI: 10.1016/j.bpa.2020.05.002 -
Neurochemistry International Jan 2023S-adenosyl-l-methionine (SAMe), a methyl donor, induces antidepressant effects in preclinical and clinical studies of depression. However, the mechanisms behind these...
S-adenosyl-l-methionine (SAMe), a methyl donor, induces antidepressant effects in preclinical and clinical studies of depression. However, the mechanisms behind these effects have been poorly investigated. Since SAMe is involved in monoamine metabolism, this work aimed at 1) testing the effects induced by systemic treatment with SAMe in mice submitted to the forced swimming test (FST) and tail suspension test (TST); 2) investigating the involvement of serotonergic neurotransmission in the behavioral effects induced by SAMe. To do that, male Swiss mice received systemic injections (1 injection/day, 1 or 7 days) of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), SAMe (10, 25, 50, 100, and 200 mg/kg), or vehicle (10 ml/kg) and were submitted to the FST or TST, 30 min after the last injection. The effect of SAMe (50 mg/kg) was further investigated in independent groups of male Swiss mice pretreated with p-chlorophenylalanine (PCPA, serotonin synthesis inhibitor, 150 mg/kg daily, 4 days) or with WAY100635 (5-HT receptor antagonist, 0.1 mg/kg, 1 injection). One independent group was submitted to the FST and euthanized immediately after for collection of brain samples for neurochemical analyses. Serotonin (5-HT) and noradrenaline (NA) levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC). Furthermore, to investigate if the treatments used could induce any significant exploratory/motor effect which would interfere with the FST results, the animals were also submitted to the open field test (OFT). The administration of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), and SAMe (10 and 50 mg/kg) reduced the immobility time in the FST, an effect blocked by pretreatment with PCPA and WAY100635. None of the treatments increased the locomotion in the OFT. In conclusion, our results suggest that the antidepressant-like effects induced by SAMe treatment are dependent on serotonin synthesis and 5-HT receptor activation.
Topics: Male; Mice; Animals; Serotonin; S-Adenosylmethionine; Imipramine; Depression; Receptor, Serotonin, 5-HT1A; Antidepressive Agents; Serotonin Antagonists; Selective Serotonin Reuptake Inhibitors; Swimming
PubMed: 36402294
DOI: 10.1016/j.neuint.2022.105442 -
European Journal of Medicinal Chemistry Dec 20195-HT receptors are the most recently discovered serotonergic receptors, for which numerous physiological implications in the central and the peripheral nervous systems... (Review)
Review
5-HT receptors are the most recently discovered serotonergic receptors, for which numerous physiological implications in the central and the peripheral nervous systems as well as the endocrine system are described. A current public health challenge is to propose new and more efficient treatments against neuropsychiatric disorders such as epilepsy or Alzheimer's disease. In this context, 5-HT receptors represent an interesting target for the treatment and prevention of those pathologies, as an alternative or in association with other medicines. Thus, numerous chemical series of agonists and antagonists have been developed. Some of these molecules have shown a therapeutic potential in various in vivo studies. This review aims to present an overview of 5-HT receptors and of the medicinal chemistry programs that led to the identification of new, potent and selective 5-HT receptors ligands. Structure-activity relationships studies based on molecular docking and pharmacophoric approaches are also described.
Topics: Animals; Humans; Ligands; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Structure-Activity Relationship
PubMed: 31581003
DOI: 10.1016/j.ejmech.2019.111705 -
CNS & Neurological Disorders Drug... 2020Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the... (Review)
Review
Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the serotonin 5HT2A receptors, dopamine D2 and D1 receptors and the serotonin transporter. It has a unique mechanism of action because it simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, implicated in serious mental illness. It can be considered a multi-target-directed ligand and a multifunctional modulator of serotoninergic system with possible precognitive, antipsychotic, antidepressant and anxiolytic properties. Lumateperone has been investigated as a novel agent for the treatment of schizophrenia, but it represents a new potential option for other psychiatric and neurological diseases, such as behavioural symptoms of dementia or Alzheimer's disease, sleep disturbances, bipolar depression. Besides, it has demonstrated a favourable safety profile without significant extrapyramidal side effects, hyperprolactinemia or changes in cardiometabolic or endocrine factors versus placebo. Additional studies are warranted to confirm and examine the benefit of lumateperone and possible therapeutic targets. This paper is a comprehensive and thorough summary of the most important findings and potential future role of this particular compound in personalized treatments.
Topics: Alzheimer Disease; Bipolar Disorder; Dementia; Dopamine D2 Receptor Antagonists; Drug Partial Agonism; Heterocyclic Compounds, 4 or More Rings; Humans; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Sleep Wake Disorders
PubMed: 32479249
DOI: 10.2174/1871527319666200601145653 -
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 -
Journal of Medicinal Chemistry Sep 20215-HTR belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of...
5-HTR belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HTR ligands, we designed and synthesized a series of pyrazolyl-diazepanes and pyrazolyl-piperazines , which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and β-arrestin signaling pathways of 5-HTR. Among them, 1-(3-(3-chlorophenyl)-1-pyrazol-4-yl)-1,4-diazepane showed the best binding affinity for 5-HTR and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with in vivo with Shank3 transgenic (TG) mice, wherein significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HTR could be a potential therapeutic target for treating autism spectrum disorder stereotypy.
Topics: Animals; Autistic Disorder; Drug Design; Grooming; Male; Mice, Transgenic; Microfilament Proteins; Molecular Docking Simulation; Nerve Tissue Proteins; Pyrazoles; Receptors, Serotonin; Serotonin Antagonists
PubMed: 34519505
DOI: 10.1021/acs.jmedchem.1c01093 -
Journal of Natural Products Sep 2022Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HTR ligands.... (Review)
Review
Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HTR ligands. 1,2,9,10-Tetraoxygenated aporphine alkaloids in particular have demonstrated good affinity for 5-HTRs. In continued efforts to understand the impacts of structural modification of the 1,2,9,10-tetraoxygenated aporphine template on affinity, selectivity, and activity at 5-HTR subtypes, we used (+)-boldine () as a semisynthetic feedstock in the preparation of C-2-alkoxylated (+)-predicentrine analogues. Compound , which contains a benzyloxy group at C-2, has been identified as a novel 5-HTR ligand with strong affinity (4 nM) and moderate selectivity versus 5-HTR and 5-HTR (12-fold and 6-fold, respectively). Compound functions as an antagonist at 5-HT and 5-HT receptors. Computational experiments indicate that several hydrophobic interactions as well as strong H-bond and salt bridge interactions between the protonated amine moiety in and Asp134 are responsible for the potent 5-HTR affinity of this compound. Furthermore, compound displays favorable predicted drug-like characteristics, which is encouraging toward future optimization.
Topics: Aporphines; Caco-2 Cells; Humans; Ligands; Serotonin 5-HT2 Receptor Antagonists
PubMed: 36001775
DOI: 10.1021/acs.jnatprod.2c00365 -
Acta Neuropsychiatrica Jun 2021Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating...
OBJECTIVE
Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear.
METHODS
Male Sprague-Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only.
RESULTS
The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear.
CONCLUSION
Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.
Topics: Animals; Anxiety; Behavior, Animal; Conditioning, Psychological; Disease Models, Animal; Fear; Fenclonine; Freezing Reaction, Cataleptic; Male; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists
PubMed: 33593455
DOI: 10.1017/neu.2021.3 -
Microvascular Research Jan 2023The objective of the present study was to evaluate the effects and safety of sarpogrelate hydrochloride (sarpogrelate) in patients with elevated blood viscosity (BV),...
The objective of the present study was to evaluate the effects and safety of sarpogrelate hydrochloride (sarpogrelate) in patients with elevated blood viscosity (BV), after 12 and 24 weeks of twice (BID) or thrice (TID) daily administrations of sarpogrelate (100 mg). The participants received oral sarpogrelate administration for 24 weeks and visited the hospital every 12 ± 2 week for blood viscosity measurements at shear rates of 5 and 300 s. The BV measured at shear rate of 5 s in male patients decreased significantly from 18.91 cP at the baseline to 16.3 cP after 24 weeks of sarpogrelate administration (13.6 % drop, p < 0.001). The BV measured at 5 s in female decreased more significantly from 17.5 cP at the baseline to 13.4 cP after 24 weeks of sarpogrelate administration (23.0 % drop, p < 0.001). In summary, sarpogrelate may be considered as a possible therapeutic option for improving BV in patients with elevated blood viscosity. In particular, the reduction of the low-shear BV with the help of a viscosity-reducing drug such as sarpogrelate may be considered as a potentially new pharmacological tool for microvascular disease.
Topics: Humans; Male; Female; Blood Viscosity; Succinates; Serotonin Antagonists; Platelet Aggregation Inhibitors
PubMed: 36126755
DOI: 10.1016/j.mvr.2022.104439 -
International Journal of Molecular... Feb 2022While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million...
While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.
Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Duloxetine Hydrochloride; Hemostasis; Humans; Mice; Norepinephrine; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Serotonin; Serotonin Antagonists; Thrombosis
PubMed: 35269729
DOI: 10.3390/ijms23052587