• MeSH
• 17-hydroxykortikosteroidy moč   MeSH
• dítě MeSH
• lidé MeSH
• metody MeSH
• metyrapon * MeSH
• mladiství MeSH
• obezita * etiologie   moč   MeSH
• systém hypotalamus-hypofýza MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 17-hydroxykortikosteroidy MeSH
• metyrapon * MeSH

The blood-brain barrier plays a vital role in the protection of the central nervous system. It is composed of endothelial cells with tight-junctions to limit the penetration of many endogenous and exogenous compounds, particularly hydrophilic xenobiotics. Nerve agents and pesticides are groups of compounds with high penetration potential into the central nervous system. However, oxime type antidotes are known to penetrate blood-brain barrier only in low concentration. The aim of presented study is to describe the pharmacokinetic profile of oxime K027 a novel antidote candidate. The main focus is on penetration of tested substance into the selected brain regions following time-dependent manner. The maximum concentration of the oxime K027 was attaining 15 and 30 min after i.m. application in plasma and brain tissue, respectively. The perfused brain tissue concentration was relatively high (10(-7) M order of magnitude) and depending on the brain region it was constant 15-60 min after application. The highest concentration was found in the frontal cortex 15 min after application while the lowest measured concentration was determined in the basal ganglia. This study showed that oxime K027 is able to achieve high concentration level in perfused brain tissue relatively quickly, but also demonstrated rapid clearance from the central nervous system. These results are probably due to low overall uptake of oxime K027 into the brain.

• MeSH
• časové faktory MeSH
• centrální nervový systém účinky léků   metabolismus   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• mozek účinky léků   metabolismus   MeSH
• oximy metabolismus   farmakokinetika   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny metabolismus   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• oximy MeSH
• pyridinové sloučeniny MeSH

Up to now, intensive attempts to synthesize a universal reactivator able to reactivate cholinesterases inhibited by all types of nerve agents/organophosphates were not successful. Therefore, another approach using a combination of two reactivators differently reactivating enzyme was used: in rats poisoned with tabun and treated with combination of atropine (fixed dose) and different doses of trimedoxime and HI-6, changes of acetylcholinesterase activities (blood, diaphragm and different parts of the brain) were studied. An increase of AChE activity was observed following trimedoxime treatment depending on its dose; HI-6 had very low effect. Combination of both oximes showed potentiation of their reactivation efficacy; this potentiation was expressed for peripheral AChE (blood, diaphragm) and some parts of the brain (pontomedullar area, frontal cortex); AChE in the basal ganglia was relatively resistant. These observations suggest that the action of combination of oximes in vivo is different from that observed in vitro.

• MeSH
• acetylcholinesterasa krev   metabolismus   MeSH
• aktivace enzymů účinky léků   MeSH
• centrální nervový systém účinky léků   enzymologie   metabolismus   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu Rattus MeSH
• organofosfáty MeSH
• otrava organofosfáty * MeSH
• oximy aplikace a dávkování   farmakologie   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   farmakologie   MeSH
• reaktivátory cholinesterasy aplikace a dávkování   farmakologie   MeSH
• trimedoxim aplikace a dávkování   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• asoxime chloride MeSH Prohlížeč
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• tabun MeSH Prohlížeč
• trimedoxim MeSH

Dysfunction of the androgen receptor (AR) signalling axis plays a pivotal role in the development and progression of prostate cancer (PCa). Steroidal and non-steroidal AR antagonists can significantly improve the survival of PCa patients by blocking the action of the endogenous ligand through binding to the hormone receptor and preventing its activation. Herein, we report two synthetic strategies, each utilizing the advantages of microwave irradiation, to modify the A-ring of natural androgen 5α-dihydrotestosterone (DHT) with pyridine scaffolds. Treatment of DHT with appropriate Mannich salts led to 1,5-diketones, which were then converted with hydroxylamine to A-ring-fused 6'-substituted pyridines. To extend the compound library with 4',6'-disubstituted analogues, 2-arylidene derivatives of DHT were subjected to ring closure reactions according to the Kröhnke's pyridine synthesis. The crystal structure of a monosubstituted pyridine product was determined by single crystal X-ray diffraction. AR transcriptional activity in a reporter cell line was investigated for all novel A-ring-fused pyridines and a number of previously synthesized DHT-based quinolines were included to the biological study to obtain information about the structure-activity relationship. It was shown that several A-ring-fused quinolines acted as AR antagonists, in comparison with the dual or agonist character of the majority of A-ring-fused pyridines. Derivative 1d (A-ring-fused 6'-methoxyquinoline) was studied in detail and showed to be a low-micromolar AR antagonist (IC50 = 10.5 µM), and it suppressed the viability and proliferation of AR-positive PCa cell lines. Moreover, the candidate compound blocked the AR downstream signalling, induced moderate cell-cycle arrest and showed to bind recombinant AR and to target AR in cells. The binding mode and crucial interactions were described using molecular modelling.

• Klíčová slova
• Androgen receptor, Crystal structure, Dihydrotestosterone, Pyridines, Transcriptional activity,
• MeSH
• androgenní receptory metabolismus   MeSH
• antagonisté androgenních receptorů farmakologie   MeSH
• dihydrotestosteron * farmakologie   metabolismus   MeSH
• lidé MeSH
• mikrovlny MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * farmakoterapie   metabolismus   MeSH
• pyridiny farmakologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androgenní receptory MeSH
• antagonisté androgenních receptorů MeSH
• dihydrotestosteron * MeSH
• pyridiny MeSH