RNDr. Hana Chodounská, CSc.

Grant of the Academy of Sciences No. IAA4055305

Neurosteroids which act on NMDA, GABA_A and other receptors, alter the course of many psychiatric and neurologic disordes. Similar compounds with longer biological half-life could be useful in the treatment of such illnesses. We prepared a series of compounds more water soluble and more metabolically stable than natural neurosteroids. Their activity was studied on subcellular systems and structure was changed according to the results of biological tests. Activity of the derivative tested in vivo was surprisingly low. The goal of the submitted project is to work up methods of preparation of steroid derivatives with hydrophilic substituents in convenient positions of the skeleton which can increase the hydrophilic properties and metabolic stability of the molecule and do not inhibit its binding to the receptor and ability to modulate receptor activity. The activity of the products will be assayed by receptor binding studies and in vivo experiments.

MUDr. Ladislav Vyklický Jr., PhD., DrSc. and RNDr. Hana Chodounská, CSc.

Grant Agency of the Czech Republic (grant No. 309/04/1537)

Mechanism of action of PS using whole-cell patch-clamp recordings from hippocampal neurons and human embryonic kidney HEK293 cells transfected with NR1 and NR2B subunits of the NMDA receptor is studied. Results suggest that PS has a positive modulatory effect at NMDA receptors that is due to increase in the channels open probability (Po), and furthermore that the binding/unbinding of PS from the receptor is slow and influenced by receptor activation.

RNDr. Alexander Kasal, DrSc. and Prof. MUDr. Pavel Mareš, DrSc.

Grant Agency of the Czech Republic (grant No. 203/06/1605)

Epilepsies represent a hot topic in neurology. Their prevalence is 0.5-1 % in developed countries, reliable data for developing countries are not accessible but higher percentage has to be expected. In spite of the treatment with classical and modern antiepileptic drugs approximately 25% of patients are resistant to therapy. Even in patients with good efficacy of antiepileptics, side effects of these drugs can decrease quality of life. In addition, antiepileptic drugs are in fact only anticonvulsants because they are only able to suppress seizures but not to cure epilepsy. They are also unable to prevent development of epilepsy after brain injury or ischemic attack.

Our aim is to prepare and test biological activity of new types of neuroactive steroids: they should have sufficient metabolic stability, their solubility in aqueous conditions should make the compounds viable for a more user-friendly application. Our optimal product should be a 3b-alkylated compound derived of 5b-neurosteroid - 3a-hydroxy-5b-pregnan-20-one with a polar side chain in position 16a. Tolerance against this 5b-derivative should be less likely compared to its 5a isomer.

RNDr. L. Kohout, DrSc.and Ing. B. Slavíková in cooperation with professor C. Brosa, PhD.

Grant of the Academy of Sciences No. A400550609: Fluoro analogues of brassinosteroids with enhanced metabolic stability, and Joint Projects (Kohout/Brosa): Brassinosteroids: Synthesis and structure-activity relationship and (Suňol/Kasal/Brosa/Coll/Kohout): Study of the Biological Activity of neurosteroids and synthesis of new steroid analogues

Brassinolide is very expensive and therefore without any chance to be used in practice. Further, almost nothing is known about its physiological activity. Structure-activity relationships of brassinolide-type plant growth regulators (brassinosteroids), known up to now, are ambiguous; some of them are even contradictory. Our effort is directed to formulation of the structure activity relationship of plant growth regulators with brassinolide activity. New types of brassinolide analogues have been and are now synthesized with modified positions, which are essential for brassinolide activity. Their activity is to be evaluated in several different bioassays, the second bean internode bioassay, the rice lamina inclination test, and - what is the most important - in the field. This activity is supported above given projects. We cooperate in our research with research centres as in Czech Republic (e.g. Institute of Experimental Botany of ASCR, Faculty of Natural Sciences of Charles University. Polytechnical University in Prague etc.) as abroad (e.g. Institut Químic de Sarriá, University Ramon Llull, Barcelona, Max-Planck Institute in Cologne etc.).

Prof. T. Macek, PhD., and RNDr. L. Kohout, DrSc.

Grant of the Academy of Sciences No. A4055204

We described that not only different bioassays afford different results but also they are often not in accordance with field test. Therefore we endeavour to find which type of plant proteins binds to brassinosteroids. This would be helpful to understand the way of action of brassinosteroids as well as to suggest the convenient compound with high activity for practical use. This part of our research is done under the project "Utilization of affinity chromatography for identification of sterol binding plant proteins".

RNDr. L. Kohout, DrSc., RNDr. Dana Holá, PhD. (Charles University)), RNDr. N. Wilhelmová, PhD. (Institute of Experimental Botany AVCR), Ing. L. Bláha, PhD. (Research institute of Plant Production, Prague) and J. Havel (VUOL, Opava)

National Agency for Agricultural Research, project No. NAZV-3056: Influence of brassinsteroids on plant stress; Grant of the Academy of Sciences No. 1QS510680561: New type of preparations influencing of plant growth and No. B601110611: Brassinosteroids as physiological process regulators in corn under optimal and stress conditions

Removing of plant stress is the next topic we are devoting to. This research is done in cooperation especially with Faculty of Natural Sciences of Charles University, Prague, Institute of Experimental Botany of ASCR, and two Resort Research Institutes (Prague, Opava). However, brassinosteroids are active not only in preventing plant stress. Especially important seems to be stress of insufficient amount of water and/or high temperature. Our first results show that brassinosteroids are able to control water economy in plants. These studies are supported by above mentioned grants.

Prof. RNDr. Pavel Drašar, DSc. (IOCB and Institute of Chemical Technology, Prague) and Prof. RNDr. Vladimír Král, CSc. (IOCB and Institute of Chemical Technology, Prague)

Project COST D-31: Organising Non-Covalent Chemical Systems with Selected Functions, 2003-2009, Natural Products as Function Modifiers in Non-Covalent Supramolecular Systems (NPFM) No. 1P04OCD31.001, 2004-2008. Grant GA ČR 203/06/0006, Synthesis and study of chiral supramolecular synthons (SSCSS), 2006-2009.

Unique steroid stereochemistry and possibilities of selective and stereo-controlled substitution of the skeleton are offering a challenge of utilization of steroids within the systems capable of specific interactions.

As a system of choice, there was selected cyclic pyrrole heterocycle of porphyrin and calix[n]pyrrole types with steroid substitutions in meso positions. The aim of the project is to attach to the macrocycle such a steroid, which could complex different target substrates.

Basic synthetic procedures were already covered by a patent application and published. Our aim is to utilize the potential of steroid synthesis in this challenging branch of organic synthesis. Recently, there are several parallel attempts to synthesize sterically organized receptors for recognition of biologically active substrates.