Slavikova Barbora has received her Master’s degree in 1983 from the Institute of Chemical Technology in Prague. She has been working at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic in Prague for almost 25 years with specialization in steroidal synthesis. During this period, she has synthesized thousands of compounds and is the author and co-author in 18 original papers and 4 patents.
Our main avenue of investigation is design and synthesis of steroidal inhibitors of N-methyl-D-aspartate receptors (NMDAR) that could serve as drug-like candidates for CNS disorders as these receptors are essential for synaptic plasticity, learning and memory. However, under pathological conditions, the over-excitation of the NMDAR can induce cell death. Our ongoing structure-activity relationship studies (SAR) are focused on structural modifications of steroidal skeleton that would afford potent inhibitors of NMDAR. In general, the inhibitory effect of neurosteroids on NMDAR is dependent upon the 5β-pregnane skeleton. To elucidate the SAR of the pregnane acetyl moiety, we have prepared a series of compounds with lipophilic D-ring modifications and showed that these analogues are more potent modulators of NMDA-induced currents (IC50 values varying from 90 nM to 5.4 μM) than the known endogenous neurosteroid- pregnanolone sulfate (IC50=24.6 μM). The obtained results emerged us to assess the structural motif of the steroidal D-ring. As such, a series of compounds with partially of fully degraded D-ring was synthesized (IC50 values varying from 15 μM to 224 μM). Finally, using the total synthesis of steroidal A, B and C-ring, we have prepared a series of compounds with non-steroidal structural characteristics of various types that allowed us to define new structural motifs for inhibitors of NMDA receptors.
Elena Solntseva graduated from the Lomonosov Moscow State University (Moscow, Russia) with a degree "neuroscience". She then worked at the Center for Mental Health in Moscow, where she defended her PhD thesis and then a Doctoral thesis. She currently works at the Research Center of Neurology in Moscow. She is the author of dozens of scientific publications.
Lithium salts are successfully used to treat bipolar disorder. At the same time, according to recent data lithium may be considered as a candidate medication for the treatment of neurodegenerative disorders. The mechanisms of therapeutic action of lithium have not been fully elucidated. In particular, in the literature there are no data on the effect of lithium on the glycine receptors. In the present study we investigated the effect of Li+ on glycine-activated chloride current (IGly) in rat isolated pyramidal hippocampal neurons using patch-clamp technique. Short (600 ms) application of Li+ caused two effects: (1) an acceleration of desensitization (a decrease in the time of half-decay, or “τ”) of IGly and (2) a reduction of the peak amplitude of the IGly, Both effects were not voltage-dependent. Dose-response curves for both effects were N-shaped with two maximums at 100nM and 1mM of Li+ and a minimum at 1 μM of Li+. This complex form of dose-response may indicate that the process activated by high concentrations of lithium inhibits the process that is sensitive to low concentrations of lithium. Longer application (10 min) of Li+ caused similar effects, but in this case 1μM lithium was effective and the dose-effect curves were not N-shaped. The inhibitory effect of lithium ions on glycine-activated current suggests that lithium in low concentrations is able to modulate tonic inhibition in the hippocampus. This important property of lithium should be considered when using this drug as a therapeutic agent.