Background The hypocretin/orexin system has been shown to play a role in heart failure. Whether it also influences myocardial infarction (MI) outcomes is unknown. We evaluated the effect of the rs7767652 minor allele T associated with decreased transcription of the hypocretin/orexin receptor-2 and circulating orexin A concentrations on mortality risk after MI. Methods and Results Data from a single-center, prospectively designed registry of consecutive patients hospitalized for MI at a large tertiary cardiology center were analyzed. Patients without previous history of MI or heart failure were included. A random population sample was used to compare allele frequencies in the general population. Out of 1009 patients (aged 64±12 years, 74.6% men) after MI, 6.1% were homozygotes (TT) and 39.4% heterozygotes (CT) for minor allele. Allele frequencies in the MI group did not differ from 1953 subjects from general population (χ2P=0.62). At index hospitalization, MI size was the same, but ventricular fibrillation and the need for cardiopulmonary resuscitation were more prevalent in the TT allele variant. Among patients with ejection fraction ≤40% at discharge, the TT variant was associated with a lower increase in left ventricular ejection fraction during follow-up (P=0.03). During the 27-month follow-up, there was a statistically significant association of the TT variant with increased mortality risk (hazard ratio [HR], 2.83; P=0.001). Higher circulating orexin A was associated with a lower mortality risk (HR, 0.41; P<0.05). Conclusions Attenuation of hypocretin/orexin signaling is associated with increased mortality risk after MI. This effect may be partially explained by the increased arrhythmic risk and the effect on the left ventricular systolic function recovery.
YNT-185 is the first known small molecule acting as orexin 2 receptor (OX2R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX2R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX2R. We obtained seven new potential OX2R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX2R. Out of them, 15 emerged as the most potent modulator of OX2R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.
- MeSH
- aniliny farmakologie terapeutické užití MeSH
- benzamidy farmakologie terapeutické užití MeSH
- lidé MeSH
- molekulární struktura MeSH
- orexinové receptory terapeutické užití MeSH
- poruchy iniciace a udržování spánku farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1−L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC50 of 2.2 μM, offering some promise mainly for the treatment of insomnia.
- MeSH
- antagonisté orexinových receptorů chemie farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- inhibiční koncentrace 50 MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- ligandy MeSH
- molekulární konformace MeSH
- molekulární modely * MeSH
- molekulární struktura MeSH
- orexinové receptory chemie MeSH
- orexiny chemie farmakologie MeSH
- počítačová simulace * MeSH
- racionální návrh léčiv * MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
1 svazek : ilustrace a tabulky ; 30 cm
Recently an increasing number of studies have been exploring the interrelations among appetite regulating peptides (ARP), food-intake disorders and drug dependencies with a hope for finding a new treatment approach to addiction. A number of studies support this supposal, particularly in alcoholism, however, in opioid dependence these interrelations has been only rarely studied yet. Thus, in the project we want to study the role of ghrelin, orexin, insulin, leptin in the opioid (morphine, fentanyl) dependence, using the experimental models of (i) abstinence syndrome, (ii) relaps, (iii) fear and anxiety. At these models (mice, rats) the presumed ?therapeutic? effects of ghrelin and orexin antagonists will be tested. (i) Behavioural (explorative locomotion; aversive vocalization; elevated plus maze) (ii) molecular (measurement of ARP plasma concentrations) and (iii) neurochemical (CNS microdialysis in vivo) methods will be used. In the clinic the data in alcoholics and heroin addicts will be completed.
Aktuálně vzrůstá počet prací jež zkoumají vztahy mezi hormony ovlivňujícími apetit (appetite regulating peptides; ARP), poruchami příjmu potravy a drogovými závislostmi s nadějí, že studium povede k nalezení nového léčebného přístupu k závislostem. Řadastudií tento předpoklad podporuje zejména u alkoholismu, u opiátové závislosti jsou tyto vztahy dosud minimálně probádané. Proto chceme v projektu studovat úlohu ghrelinu, orexinu, insulinu a leptinu u opiátové závislosti (morfin, fentanyl), v experimentálních modelech (i) abstinenčního syndromu, (ii) relapsu, (iii) strachu a úzkostí provázejících závislost. V těchto modelech (myši, potkani) ověříme předpokládaný ?léčebný? efekt antagonistů ghrelinu a orexinu. K testování vztahů užijeme metody (i) behaviourální (explorační lokomoce; test aversivní vokalizace; vyvýšené bludiště), (ii) molekulární (měření plazmatických koncentrací vybraných ARP), (iii) neurochemické (CNS mikrodialýza in vivo). V klinické části doplníme údaje u heroinistů a alkoholiků.
- MeSH
- abstinenční syndrom MeSH
- alkoholismus MeSH
- chuť k jídlu MeSH
- ghrelin MeSH
- klinické lékařství MeSH
- modely u zvířat MeSH
- orexinové receptory MeSH
- peptidové hormony MeSH
- poruchy příjmu potravy MeSH
- poruchy spojené s užíváním opiátů MeSH
- recidiva MeSH
- terapie MeSH
- uživatelé drog MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- nutriční terapie, dietoterapie a výživa
- biochemie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
- Klíčová slova
- pandemie prasečí chřipky, vakcína Pandemrix, vakcína stažena z trhu, protein hypokretinového receptoru 2,
- MeSH
- antagonisté orexinových receptorů MeSH
- hodnotící studie jako téma MeSH
- lidé MeSH
- narkolepsie * diagnóza genetika chemicky indukované komplikace prevence a kontrola MeSH
- orexinové receptory fyziologie imunologie účinky léků MeSH
- protilátky virové biosyntéza diagnostické užití farmakologie krev škodlivé účinky MeSH
- vakcíny proti chřipce * analýza aplikace a dávkování farmakologie škodlivé účinky terapeutické užití MeSH
- virové proteiny * aplikace a dávkování diagnostické užití farmakologie chemie izolace a purifikace škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- Klíčová slova
- hypokretiny, orexin-A (hypokretin-1), orexin-B (hypokretin-2),
- MeSH
- energetický metabolismus fyziologie MeSH
- lidé MeSH
- narkolepsie * etiologie MeSH
- neuropeptidy * biosyntéza fyziologie sekrece MeSH
- obezita etiologie MeSH
- orexinové receptory MeSH
- regulace chuti k jídlu * fyziologie MeSH
- stravovací zvyklosti fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
