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TRPA1 is an ankyrin receptor of TRP family. It is mostly expressed in the smalldiameter nociceptors with cell bodies located in the dorsal roots, as well as in trigeminal, nodose and jugular ganglia. Recently, more and more information has been found in the literature on the role of TRPA1 in the realization of cold and pain sensitivity, and also in the formation and maintenance of inflammation. Subject to these data there is an increasing interest in finding and studying pharmacological agents able to selectively block the TRPA1 receptors and thereby reduce the severity of pain and inflammation. Using the molecular modeling techniques, we analyzed spectra of biological activity of a series of promising candidates for selective antagonists of TRPA1 ion channel in order to find potentially active compounds against pain and inflammation. Substances that showed in high throughput screening the percentage of the cellular calcium response inhibition above 50% - 3*SD maximum and its own agonistic activity less than 10% + 3*SD minimum were identified as hits. The value IC50 for hits was determined immediately after re-testing at 10 μM concentration and repeatedly after the determination of the leading chemical series. As the result of the studies, the biologically active molecules of leading chemical series have been confirmed. The research was partially supported by the grant of the President of the Russian Federation №MD-4711.2015.7 and МК-6135.2016.4.

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Depolarization automaticity was modeled on the papillary muscle from the guinea pig heart. Phosphoenolpyruvate (0.1 mM) 2-fold decreased the high-frequency calcium-dependent automaticity, but only weakly affected frequency of action potentials, whose upstroke was formed by fast sodium current or had a mixed nature. Phosphoenolpyruvate shifted the diastolic potential toward negative values, which depended on the amplitude of depolarization step. These effects developed 10-15 min after application of the preparation.Key Words: phosphoenolpyruvate; depolarization automaticity; action potential Glycolysis intermediates produced pronounced antiischemic and antiarrhythmic effect in animals with acute coronary occlusion and reperfusion [ 1,8,9,11 ]. Taking into consideration the involvement of cell metabolism in the genesis of cardiac arrhythmias [5,12], the antiarrhythmic effect of these substances can be explained by prolongation of the glycolytic energy production in cardiomyocytes [3,6,7]. However, participation of common electrophysiological mechanisms [13] in the antiarrhythmic effect of glycolysis intermediates was not yet assessed.Our aim was to study the effect of phosphoenolpyruvate (PEP) on electrical activity of isolated myocardial ventricles. MATERIALS AND METHODSThe study was carried out on guinea pigs weighing 250-350 g. The papillary muscles were isolated from the right ventricle under nembutal narcosis. The muscle were mounted in a chamber (2 ml) and perfused with oxygenated Tyrode solution (35~ pH 7.4) containing (in mM): 130 NaCI, 2.7 KC1, 2.0 CaCl2, 1.0 MgC12, 10 glucose, and 5 HEPES-NaOH.Membrane potential was measured with 10-20-M.Q glass microelectrodes. The signal and its first derivative were recorded with an automatic differentiator Department of Pharmacology, Mordovian State University, Saransk (Micromed). The duration of action potentials (AP) corresponding to 50 and 90% repolarization was measured. The preparations were stimulated with the trains of rectangular pulses applied via bipolar silver electrodes. The duration and frequency of pulses in the train were 1 msec and 1 Hz, respectively.The depolarization automaticity was modeled according to [2]. The rectangular direct current impulses were applied at a rate of 1 Hz via silver-chloride electrodes and an agar salt bridge from an ESU-2 electric stimulator (4.5-6.5 sec pulse duration), Membrane potential was recorded by the same method.In this study we used PEP tricyclohexylammonium salt (Sigma). RESULTSInitially we evaluated the effect of PEP on some parameters of AP in persistently stimulated guinea pig papillary muscle. PEP (0.1 mM) produced a moderate, but significant decrease in AP duration by l 1 and 7% at the 50 and 90% repolarization level, respectively. These changes developed 3-5 min after application of PEP in Tyrode solution and reached a steady-state level after 10-15 min. The PEP-induced shortening of AP became reversible only after 30-60-min washout. The test substance did not change resting potential, AP amplitude, and maxim...

Data on the syntheses and structures of a series of new derivatives of 2-diethylamino-2¢,6¢-dimethylphenylacetamide are described. The results of an experimental study of the new compounds on various arrhythmia models in animals are presented. Several substances effectively preventing the onset of ventricular ischemia, reperfusive and toxic fibrillation, and ischemic arrhythmia have been selected, which are superior to the reference drug lidocaine with respect to their antiarrhythmic properties.