- MeSH
- chemie organická dějiny metody MeSH
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- farmaceutická technologie dějiny metody trendy MeSH
- lidé MeSH
- nemoci nervového systému farmakoterapie MeSH
- steroidy * dějiny chemie MeSH
- Check Tag
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- lidé MeSH
- Publikační typ
- historické články MeSH
Neuroactive steroids represent potential antiepileptic drugs. We tested a newly synthesized analogue of allopregnanolone 3?- hydroxy-21?,22-oxido-21-homo-5?-pregnan-20-on (HOHP) against two types of pentylenetetrazol-induced seizures (100 mg/kg s.c.) in 12- and 25-day-old rats. Ganaxolone, a neuroactive steroid in clinical trials, served as a reference drug. Pretreatment with either steroid suppressed generalized tonicclonic seizures in both age groups, their efficacy was comparable. HOHP as well as ganaxolone were more active in 12- than in 25-day-old rats (effective doses were 40 and 60 mg/kg, respectively). Minimal clonic seizures, which can be elicited only in 25-day-old rats, were not influenced by any drug. Very short duration of anticonvulsant action of HPOP demonstrated in 12-day-old animals indicates that this drug might be used only in acute treatment in epileptology.
The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by previously prepared allopregnanolone with a 16alpha-bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16alpha with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids. The Michael addition to derivatives of pregn-16-en-20-one was the key reaction step. The link between the steroid skeleton and the new side chain was either a methylene group (when diethyl malonate was added) or an oxygen atom (when a hydroxy derivative was added). [(35)S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABA(A) receptors. Although none of them was more potent than the above ammonium salt, which stimulated this study, their nonionic nature should not prevent their passage into the brain.
- MeSH
- financování organizované MeSH
- GABA modulátory farmakologie chemická syntéza MeSH
- krysa rodu rattus MeSH
- mozek metabolismus MeSH
- potkani Wistar MeSH
- pregnanolon analogy a deriváty farmakologie chemická syntéza MeSH
- radioligandová zkouška MeSH
- receptory GABA-A metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
Three types of 5alpha-androstane and ergostane analogues of brassinolide, containing a fluorine atom in either the 3alpha or the 5alpha positions or in 3alpha and 5alpha positions, were prepared using standard operations (reaction of 3beta-alcohols with (diethylamino)sulfur trifluoride, cleavage of epoxide with HF in py or BF 3.Et 2O). The 5alpha-fluorine was found to affect chemical reactivity (e.g., electrophilic addition to the Delta (2)-double bond) as well as physical properties (e.g., NMR, chromatographic behavior) of the products. Cytotoxicity of the products was studied using human normal and cancer cell lines with 28-homocastasterone as positive control and their brassinolide type activity was established using the bean second-internode test with 24-epibrassinolide as standard. The equivalence of F and OH groups was observed in some of the active compounds. The anticancer and the brassinolide-type activity do not correlate with each other: ergostane derivatives were most active in the former test while androstane derivatives were best in the latter.
- MeSH
- antitumorózní látky farmakologie chemická syntéza chemie MeSH
- buněčné linie MeSH
- cholestanoly farmakologie chemická syntéza chemie MeSH
- financování organizované MeSH
- lidé MeSH
- molekulární struktura MeSH
- sloučeniny fluoru farmakologie chemická syntéza chemie MeSH
- steroidy heterocyklické farmakologie chemická syntéza chemie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
Anticonvulsant activity of allopregnanolone, a neurosteroid allosterically modulating GABA(A) receptor was tested in a model of motor seizures elicited by pentetrazol in immature rats. Rats 7, 12, 18, 25 or 90 days old were pretreated with allopregnanolone in doses from 5 to 40 mg/kg i.p. and 15 min later pentetrazol was injected subcutaneously in a dose of 100 mg/kg. Rats were observed in isolation for 30 min. Allopregnanolone dose-dependently suppressed both generalized tonic-clonic and minimal clonic seizures with the highest efficacy in 12-day-old rats. Anticonvulsant action was least expressed in adult animals. Duration of anticonvulsant action tested after a dose of 20 mg/kg in 12- and 90-day-old rats demonstrated markedly longer effects in young rats. Allopregnanolone compromised motor performance of rats but duration of this unwanted effect in 12-day-old rats was shorter than duration of anticonvulsant action. This difference can be important for possible clinical use of neurosteroids.
- MeSH
- anestetika farmakologie škodlivé účinky terapeutické užití MeSH
- financování organizované MeSH
- injekce subkutánní MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- pentylentetrazol MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- pregnanolon farmakologie škodlivé účinky terapeutické užití MeSH
- věkové faktory MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- záchvaty farmakoterapie chemicky indukované patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
The anticonvulsant action of two neuroactive steroids, 3?–hydroxy-5ß–pregnan-20-one (pregnanolone) and triethylammonium 3?–hydroxy-20-oxo-5?–pregnan-21-yl hydrogensuccinate (THDOC-conjugate), was tested against motor seizures induced by pentetrazol in immature rats. Five age groups (7, 12, 18 and 25 days old and adult rats) were pretreated with the steroids in doses from 2.5 to 40 mg/kg i.p. Twenty minutes later pentetrazol (100 mg/kg s.c.) was administered. Minimal seizures (clonic seizures of head and forelimb muscles with preserved righting ability) could be induced in the three older age groups. They were suppressed by pregnanolone in all these tested groups (this effect was best expressed in 18-day-old rats and decreased with age), whereas significant changes in THDOC-conjugate-pretreated animals appeared only in 18-day-old rats. Generalized tonic-clonic seizures were suppressed by both neuroactive steroids in all age groups, this effect being more marked with pregnanolone and again decreased with age. The 7- and 12-day-old rats exhibited higher sensitivity of the tonic phase so that generalized clonic seizures were observed. Duration of the effect was studied in 12- and 25-day-old animals; it was substantially shorter in the older rats than in 12-day-old animals. Both drugs exhibited an anticonvulsant action in developing rats but, unfortunately, their effect was only shortlasting.
- MeSH
- antikonvulziva aplikace a dávkování farmakokinetika MeSH
- financování vládou MeSH
- interpretace statistických dat MeSH
- pentylentetrazol analogy a deriváty farmakokinetika MeSH
- potkani Wistar MeSH
- pregnanolon farmakokinetika MeSH
- steroidy aplikace a dávkování fyziologie MeSH
- věkové skupiny MeSH
- záchvaty etiologie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : grafy ; 32 cm
Water-soluble derivatives of neuroactive steroids will be synthesized and their anxiolytic,sedative and other neuropsychotropic activities will be tested in animalis. The structure of the steroids will be modified in order to increase their solubility and their stability towards metabolic degradation. The zypes of these structural modifications will be chosen with knowledge of structural features essential for the binding to a GABAa receptor complex.
Studium účinků různých anxiolytik na myších bude rozšířeno o testování neuroaktivních steroidů. Struktura steroidů bude modifikována tak, aby byla zvýšena jejich rozpustnost ve vodě a jejich stabilita vůči metabolické degradaci. Typy modifikací budou odvozovány ze znalostí strukturních rysů esenciálních pro vazbu stereoidů na GABA receptor.
- MeSH
- anestetika celková chemická syntéza MeSH
- GABA modulátory MeSH
- pregnanolon chemická syntéza MeSH
- steroidy chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Konspekt
- Farmacie. Farmakologie
- NLK Obory
- farmacie a farmakologie
- farmacie a farmakologie
- chemie, klinická chemie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
