Neurosteroids are endogenous steroidal compounds that can modulate neuronal receptors. N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that are of particular interest, as they participate in synaptic transmission and are implicated in various processes, such as learning, memory, or long-term neuronal potentiation. Positive allosteric modulators that increase the activity of NMDARs may provide a therapeutic aid for patients suffering from neuropsychiatric disorders where NMDAR hypofunction is thought to be involved, such as intellectual disability, autism spectrum disorder, or schizophrenia. We recently described a new class of pregn-5-ene and androst-5-ene 3β-dicarboxylic acid hemiesters (2-24) as potent positive modulators of NMDARs. Considering the recommended guidelines for the early stage development of new, potent compounds, we conducted an in vitro safety assessment and plasma stability screening to evaluate their druglikeness. First, compounds were screened for their hepatotoxicity and mitochondrial toxicity in a HepG2 cell line. Second, toxicity in primary rat postnatal neurons was estimated. Next, the ability of compounds 2-24 to cross a Caco-2 monolayer was also studied. Finally, rat and human plasma stability screening revealed an unforeseen high stability of the C-3 hemiester moiety. In summary, by using potency/efficacy towards NMDARs data along with toxicity profile, Caco-2 permeability and plasma stability, compounds 14 and 15 were selected for further in vivo animal studies.
- MeSH
- androstenoly krev chemie farmakologie MeSH
- buňky Hep G2 MeSH
- cholesterol krev chemie farmakologie MeSH
- estery krev chemie farmakologie MeSH
- krysa rodu rattus MeSH
- kyseliny dikarboxylové krev chemie farmakologie MeSH
- lidé MeSH
- mentální retardace farmakoterapie metabolismus MeSH
- mitochondrie účinky léků metabolismus MeSH
- molekulární struktura MeSH
- nádorové buňky kultivované MeSH
- neurony účinky léků metabolismus MeSH
- neuroprotektivní látky krev chemie farmakologie MeSH
- poruchy autistického spektra farmakoterapie metabolismus MeSH
- potkani Wistar MeSH
- pregnenolon analogy a deriváty krev farmakologie MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory metabolismus MeSH
- schizofrenie farmakoterapie metabolismus MeSH
- stabilita léku MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Většina excitačního synaptického přenosu v savčí centrální nervové soustavě je zprostředkována ionotropními glutamátovými receptory. NMDA receptory, tvořící jednu ze tří tříd této skupiny chemicky aktivovaných iontových kanálů, se podílejí na tvorbě paměti a procesu učení a hrají roli i v etiologii nejrůznějších neurodegenerativních onemocnění. Činnost NMDA receptoru je ovlivňována mnoha faktory, jako jsou teplota, pH nebo různé modulační látky. Patří mezi ně i neurosteroidy, deriváty progesteronu syntetizované přímo v nervové tkáni z cholesterolu nebo ze steroidních prekurzorů pocházejících z periferních zdrojů. Cílem tohoto článku je shrnout výsledky pokusů zabývajících se modulací funkce NMDA receptoru steroidními látkami. Tyto studie byly prováděny v uplynulých letech na oddělení buněčné neurofyziologie Fyziologického ústavu AV ČR, v.v.i. (http://www2.biomed.cas.cz/d331/index.html), které je součástí Centra neuropsychiatrických studií (http://www.pcp.lf3.cuni.cz/cns/).
Excitatory synaptic transmission in mammalian CNS is mostly mediated by ionotropic glutamate receptors. NMDA receptors, one of three subclasses of this ligand-activated ion channels family, are involved in memory formation and learning and also play a role in the pathogenesis of various neurodegenerative diseases. NMDA receptors function is influenced by several factors, including temperature, pH or various chemical modulators. Among others, this group includes neurosteroids; progesterone derivatives, synthesised in neural tissue from cholesterol or different steroid precursors from peripheral sources. The aim of this article is to sum up the results of experiments designed to study the modulation of NMDA receptors function by steroid compounds. This work has been done at the Department of Cellular Neurophysiology of the Institute of Physiology AS CR, v.v.i. (http://www2.biomed.cas.cz/d331/eng/index_eng. html), a member of the Centre of Neuropsychiatric Studies (http://www.pcp.lf3.cuni.cz/cns/).
7-Hydroxy-metabolites of dehydroepiandrosterone (DHEA) and 3beta,17beta-androstenediol (AD) possess immunomodulatory and neuroprotective properties; therefore, the measurement of these steroids in patients with autoimmune diseases or disturbances in the CNS may be of interest. A gas chromatography-mass spectrometry (GC-MS) method for the determination of 7-hydroxy-metabolites of pregnenolone, DHEA, AD, and testosterone including the parent steroids was applied to serum samples from 12 adult men (27-66 years), 13 male adolescents (13-20 years), 5 boys (6-10 years), 15 women in the follicular phase of the menstrual cycle (22-45 years), 17 women in the luteal phase (22-45 years), and 4 girls (6-10 years). The steroids were age and sex dependent, but independent of the menstrual cycle. The ratio of the 7alpha-hydroxy-metabolites to their parent steroids were age dependent, exhibiting an increasing trend (p < 0.0001, ANOVA) from pregnenolone (5%) to AD (20%). The ratio of 7beta- to 7alpha-metabolites ranged from 0.6 to 1. These results are consistent with models suggesting 7alpha-hydroxylation of the parent steroid, conversion to a 7-oxo-steroid and finally to the 7beta-hydroxylated-metabolite. Partial correlations suggested that 7-hydroxylation might reduce the concentration of circulating androgens. Despite the three times lower concentration of AD-metabolites, their antiglucocorticoid, immunomodulatory, and neuroprotective effects may be comparable to that of DHEA based on their reported greater biological activity.
- MeSH
- androstendiol analogy a deriváty krev MeSH
- dehydroepiandrosteron antagonisté a inhibitory krev MeSH
- dítě MeSH
- dospělí MeSH
- finanční podpora výzkumu jako téma MeSH
- folikulární fáze MeSH
- hydroxylace MeSH
- lidé MeSH
- mladiství MeSH
- pregnenolon analogy a deriváty krev MeSH
- referenční hodnoty MeSH
- testosteron analogy a deriváty krev MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
