Sigma 1 receptor
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The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9 GBq/μmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.
- MeSH
- azepiny MeSH
- benzothiazoly MeSH
- lidé MeSH
- pozitronová emisní tomografie * metody MeSH
- radiofarmaka MeSH
- radioizotopy fluoru chemie MeSH
- receptor sigma-1 * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND PURPOSE: The σ-1 receptor (Sig-1R) agonist cutamesine (SA4503) enhanced functional recovery after experimental stroke with a treatment initiation window of 48 hours and chronic treatment for 28 days. We conducted a phase 2 clinical trial exploring the safety, tolerability, dose range, and functional effects of cutamesine in patients with ischemic stroke. METHODS: Subjects were randomized between 48 and 72 hours after stroke to receive cutamesine 1 mg/d, 3 mg/d, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (day 28), and at end of follow-up (day 56). RESULTS: In 60 patients, treatment with both cutamesine dosages was safe and well tolerated without significant differences in numbers of treatment emergent or serious adverse events. No significant effect was observed on the primary efficacy measure (change in National Institutes of Health Stroke Scale from baseline to day 56) or modified Rankin Scale and Barthel Index scores. Post hoc analysis of moderately and severely affected patients (baseline National Institutes of Health Stroke Scale, ≥7 and ≥10) showed greater National Institutes of Health Stroke Scale improvements in the 3 mg/d cutamesine group when compared with placebo (P=0.034 and P=0.038, respectively). A trend toward a higher proportion being able to complete a 10m timed walk was observed for cutamesine-treated subjects. CONCLUSIONS: Cutamesine was safe and well tolerated at both dosage levels. Although no significant effects on functional end points were seen in the population as a whole, greater improvement in National Institutes of Health Stroke Scale scores among patients with greater pretreatment deficits seen in post hoc analysis warrants further investigation. Additional studies should focus on the patient population with moderate-to-severe stroke. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov/show/NCT00639249. Unique identifier: NCT00639249. The EudraCT number is 2007-004840-60 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004840-60/GB).
- MeSH
- časové faktory MeSH
- cévní mozková příhoda patofyziologie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- internacionalita MeSH
- ischemie mozku patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- obnova funkce fyziologie MeSH
- piperaziny diagnostické užití farmakologie MeSH
- radioizotopy uhlíku diagnostické užití farmakologie MeSH
- receptory sigma agonisté MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
More than four decades passed since sigma receptors were first mentioned. Since then, existence of at least two receptor subtypes and their tissue distributions have been proposed. Nowadays, it is clear, that sigma receptors are unique ubiquitous proteins with pluripotent function, which can interact with so many different classes of proteins. As the endoplasmic resident proteins, they work as molecular chaperones - accompany various proteins during their folding, ensure trafficking of the maturated proteins between cellular organelles and regulate their functions. In the heart, sigma receptor type 1 is more dominant. Cardiac sigma 1 receptors regulate response to endoplasmic reticulum stress, modulates calcium signaling in cardiomyocyte and can affect function of voltage-gated ion channels. They contributed in pathophysiology of cardiac hypertrophy, heart failure and many other cardiovascular disorders. Therefore, sigma receptors are potential novel targets for specific treatment of cardiovascular diseases.
- MeSH
- kardiomyocyty účinky léků metabolismus patologie MeSH
- kardiovaskulární látky aplikace a dávkování metabolismus MeSH
- kardiovaskulární nemoci farmakoterapie metabolismus patologie MeSH
- lidé MeSH
- myokard metabolismus patologie MeSH
- receptory sigma antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
4th ed. viii, 231 s.
- MeSH
- klasifikace MeSH
- transdukce genetická MeSH
- Publikační typ
- příručky MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- biochemie
- biologie
The supposed role of cardiac sigma receptors is fine tuning of contractility. Sigma receptors affect several ionic channels and hence their signaling is reflected by the electrophysiological properties of the heart. Numerous ligands of sigma receptors are known to prolong the QT interval and therefore cause a variety of arrhythmias, including severe ones. The effects of the prototypical sigma ligand haloperidol have been studied extensively in humans as well as in various animal models, primarily after acute administration. We examined the incidence of arrhythmias, changes in heart rate, and prolongation of QT interval in isolated Langendorff-perfused rat and guinea pig hearts after they were exposed to nanomolar concentrations of haloperidol. Hearts from both untreated (acute) and pretreated (chronic) animals were investigated. While QT prolongation and arrhythmias due to haloperidol administration were observed in untreated rat and guinea pig hearts, arrhythmias were completely prevented in both species of chronically treated animals. In treated guinea pigs, the results were generally less convincing. Since the hearts were exposed to nanomolar concentration of haloperidol, we conclude that our data may be explained by desensitization of sigma receptors.
- MeSH
- elektrokardiografie účinky léků MeSH
- haloperidol farmakologie metabolismus MeSH
- krysa rodu rattus MeSH
- morčata MeSH
- potkani Wistar MeSH
- receptory sigma fyziologie účinky léků MeSH
- srdce fyziologie účinky léků MeSH
- srdeční arytmie chemicky indukované patofyziologie MeSH
- srdeční frekvence účinky léků MeSH
- torsades de pointes chemicky indukované patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- morčata MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
The aim of the present work was to study the effect of various stressors (hypoxia, cold, immobilization) on the gene expression of sigma receptors in the left ventricles of rat heart. We have clearly shown that gene expression of sigma receptors is upregulated by strong stress stimuli, such as immobilization and/or hypoxia. Nevertheless, cold as a milder stressor has no effect on sigma receptor's mRNA levels. Signalling cascade of sigma receptors is dependent on IP(3) receptors, since silencing of both, type 1 and 2 IP(3) receptors resulted in decreased mRNA levels of sigma receptors. Physiological relevance of sigma receptors in the heart is not clear yet. Nevertheless, based on the already published data we can assume that sigma receptors might participate in contractile responses in cardiomyocytes.
- MeSH
- financování organizované MeSH
- hypoxie MeSH
- imobilizace MeSH
- inbrední kmeny myší MeSH
- inositol-1,4,5-trisfosfát - receptory metabolismus MeSH
- kardiomyocyty metabolismus patologie MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- messenger RNA analýza MeSH
- myši MeSH
- potkani inbrední SHR MeSH
- regulace genové exprese MeSH
- RNA interference MeSH
- srdeční komory metabolismus patofyziologie MeSH
- terapeutická hypotermie MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
Contemporary society is characterized by rapid changes. Various epidemiological, political and economic crises represent a burden to mental health of nowadays population, which may at least partially explain the increasing incidence of mental disorders, including schizophrenia. Schizophrenia is associated with premature mortality by at least 13-15 years. The leading cause of premature mortality in schizophrenia patients is high incidence of cardiovascular diseases. The specific-cause mortality risk for cardiovascular diseases in schizophrenia patients is more than twice higher as compared to the general population. Several factors are discussed as the factor of cardiovascular diseases development. Intensive efforts to identify possible link between schizophrenia and cardiovascular diseases are made. It seems that sigma 1 receptor may represent such link. By modulation of the activity of several neurotransmitter systems, including dopamine, glutamate, and GABA, sigma 1 receptor might play a role in pathophysiology of schizophrenia. Moreover, significant roles of sigma 1 receptor in cardiovascular system have been repeatedly reported. The detailed role of sigma 1 receptor in both schizophrenia and cardiovascular disorders development however remains unclear. The article presents an overview of current knowledge about the association between schizophrenia and cardiovascular diseases and proposes possible explanations with special emphasis on the role of the sigma 1 receptor.
- MeSH
- kardiovaskulární nemoci * diagnóza epidemiologie MeSH
- kardiovaskulární systém * MeSH
- lidé MeSH
- schizofrenie * diagnóza epidemiologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
