R. Yu. Khisamutdinova

SYNTHESIS AND ANTIARRHYTHMIC ACTIVITY OF (1,3-DIMETHYL-5-NITRO-5-HEXAHYDROPYRIMIDINYL)- PROPIONIC ACID METHYL ESTER

Abstract(1,3-Dimethyl-5-nitro-5-hexahydropyrimidinyl)propionic acid methyl ester (I) was obtained with a 83% yield using a Mannich type reaction of 4-nitrobutanoic acid methyl ester with excess formalin and methylamine. It was found that compound I possesses low toxicity and shows antiarrhythmic activity on models of arrhythmia induced by intravenous injections of calcium chloride and aconitine in rats.

Synthesis and Antiarrhythmic Activity of N-(2-Hydroxyethyl)cytisine Hydrochloride and 3-(2-Hydroxyethyl)-1,5-dinitro-3-azabicyclo-[3.3.1]non-6-ene Hydrochloride

Synthetic analogs of natural 3-azabicyclo[3.3.1]nonanes have drawn the attention of researchers as potential drugs [1 – 3]. This study was aimed at the synthesis of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene (II) and N-(2-hydroxyethyl)cytosine (IV) and evaluation of the antiarrhythmic activity of these compounds in the form of hydrochlorides. The synthesis of compound II was based on the reduction of 1,3-dinitrobenzene with sodium borohydride to 1,3-dinitrocyclohexene disodium salt (I). This intermediate compound was introduced (without isolation from the reaction mixture) into the Mannich condensation reaction with formaldehyde and monoethanolamine, which led to the formation of target compound II (isolated with a 70% yield) [4].

A study of the mechanism of the antiarrhythmic action of Allapinin

Allapinin (lappaconitine hydrobromide) is a drug used for the treatment of cardiac rhythm disturbances; its properties are characteristic of class IC antiarrhythmics. The mechanism of its electrophysiological action involves the blockade of Na+ channels with a subsequent decrease of depolarization rate leading to a slowing of impulse propagation and a decrease of excitability in the conductive system of the heart. Factors underlying the side effects of Allapinin (tachycardia, arterial hypertension, impaired coordination, etc.) are currently unknown, and therefore a study of the molecular mechanisms of its action seems relevant. The target genes of the drug were identified in rats with induced aconitine arrhythmia using the commercially available Rat Neuroscience Ion Channels & Transporters RT2 Profiler™ PCR Array kit (SA Biosciences). A comparison of expression levels of 84 genes in rats treated with Allapinin, after the induction of arrhythmia by aconitine (experiment) and in physiological saline-treated arrhythmic rats (control), revealed 18 mRNAs which were up- or downregulated twofold or more in the experiment relative to the control. Allapinin was shown to stimulate the expression of genes coding for various types of K+ channels (kcna6, kcnj1, kcnj4, kcnq2, and kcnq4), Ca2+ channel (cacna1g), and vesicular acetylcholine transporter (slc18a3). A decrease in mRNA levels was detected for genes coding for K+ channels (kcne1, kcns1), a Na+ channel (scn8a), and membrane transporter genes (atp4a, slc6a9). Our data shows that Allapinin administered to animals with aconitine arrhythmia modulates the expression of genes accounting for ion current conductances involved in the formation of various phases of action potential (INa, Ito, IKs, IK1, ICaT). The effect of the drug on the levels of mRNAs coding for acetylcholine and glycine transporters suggests the involvement of these neuromediators in the mechanisms underlying the antiarrhythmic effect of Allapinin.

New (−)−Cytisine Derivatives with Nootropic Activity

The mnestic and antihypoxic effects of new derivatives of the quinolizidine alkaloid (−)-cytisine on acquisition of a conditioned passive avoidance reflex (CPAR) were studied in rats; effects on normobaric (jar) hypoxia were studied in mice. Screening studies showed that the benzamide and the N-(12-methylcytidin-3-yl)-N′-phenylurea not only improved learning and memory, but also increased the resistance of the brain to hypoxia.

Genes targets identification of 5-amino-exo-3-azatricyclo[5.2.1.02,6]decane-4-one in an in vivo model of arrhythmia

The molecular mechanisms of action of 5-amino-exo-3-azatricyclo[5.2.1.02,6]decane-4-one (P11), a compound possessing strong antiarrhythmic, nootropic, anti-inflammatory and analgesic activity, have been studied. Cardiac rhythm disturbances were modeled by administering the arrhythmogenic compound aconitin in a dose of 50 μg/kg to the animals from the control group. P-11 in a dose of 0.3 mg/kg was injected intravenously in the experimental group of animals 2 min before aconitin administration. P-11 target genes were identified using the Atlas™ Rat cDNA Expression macroarray (#7738-1, BD Biosciences, United States). Reproducible changes in the expression levels of 16 genes in the heart of rats treated with P-11 concommitantly to arrhythmia modeling in vivo were detected. The genes regulated by the substance coded for proteins of the extracellular matrix are (glypican 1, Gpc1; tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp3), intracellular signaling proteins (rho GTPase activating protein 7, Dlc1; protein tyrosine phosphatase 4a1, Ptp4a1; phosphodiesterase 4D, PDE4D; PI3-kinase regulatory subunit alpha, PIK3R1; guanine nucleotide binding protein alpha 12, Gna12), proteins involved in glycolysis (phosphofructokinase 1, Pfk1), intercellular interactions (junction plakoglobin, Jup), and hemostasis (tissue plasminogen activator, Plat), membranebound pumps and transporters (solute carrier family 16, member 1, Slc16a1; ATPase, Na+/K+ transporting, Atp1a), and others (c-fos proto-oncogene, c-fos; telomerase protein component 1, tlp; Annexin 1, anxa1). Therefore, the data concerning the selective effect of P-11 on genes coding for proteins involved in arrhythmogenesis allow for considering this compound as a promising medication for pathogenetically oriented therapy of arrhythmias.

Synthesis and pharmacological properties 4-methyl-1-(methylsulfinylmethyl)-7-thiabicyclo[3.3.1]non-3-en-2-one-7-oxide

Some representatives of the class of sulfur-containing organic compounds, including derivatives of sulfones [1], dialkyldisulfides [2], and 3-thiabicyclohexanecarboxylic acid [3], were reported to possess anti-inflammatory activity. Biological activity is also inherent in 1,2,5-thiadiazole and its condensed derivatives, which act upon central nervous system and influence tissue metabolism [4]. In continuation of our investigations into new bicyclic bis-sulfoxides, we have synthesized 4-methyl-1-(methylsulfinylmethyl)-7-thiabicyclo[3.3.1]non-3-en-2-one-7-oxide (I) and studied the anti-inflammatory and antiarrhythmic properties of this compound. The synthesis I was conducted according to the scheme depicted below. In the first step, we obtained 4-methyl-1(methylthiomethyl)-7-thiabicyclo[3.3.1]non-3-en-2-one (II) via alkylthiomethylation of propanone with a mixture of formaldehyde, methylmercaptan, and sodium sulfide in an alkaline medium [5]. In the second step, compound II was oxidized in a 28 – 30% aqueous hydrogen peroxide solution at 20°C, and the target compound I was obtained with a yield of 95%. The purity and the proposed structures of the synthesized compounds were confirmed by the results of elemental analyses and by the data of IR, H NMR, and C NMR spectroscopy (Tables 1 and 2). The IR spectra of compounds I and II exhibit absorption bands at 1656, 1618, 1624, and 1654 cm – 1 characteristic of the stretching vibrations of the C=O and C=C bonds [6]. In the C NMR spectrum of compound I, the signals from carbon atoms C (48.43 and 48.54 ppm), C (56.75 and 56.06 ppm), C (62.62 and 61.52 ppm), and C (36.08 and 35.79 ppm) are shifted toward lower fields as compared to the analogous signals in the spectrum of compound II (Table 2). In addition, almost all signals in the C NMR spectrum of compound I are doubled, which is indicative of the existence of two isomers. The spectra were assigned separately to each isomer. The appearance of a diastereomer pair is related to the presence of a chiral carbon atoms C and a pyramidal sulfoxide sulfur atom in the aliphatic substituent, which make possible the formation of two -diastereomers with R*R* and R*S* centers [7]. The H C NMR spectrum of compound I displays clearly distinguished signals due to the greater isomer and shows the signals from diastereotopic protons at C in the form of two doublets with a geminal spin – spin coupling constant of 13.3 Hz and a relative chemical shift = 0.61 ppm. For the second diastereomer, this difference is below 0.29 ppm. Based on the published data [7], the diastereomer with a greater difference of the chemical shifts is identified as the erythro isomer (Ia), while the component with a smaller value is identified as the threo isomer (Ib). Both isomers are

Nootropic Activity of a Novel (-)-Cytisine Derivative (3aR,4S,8S,12R, 12aS,12bR)-10-Methyl-2-Phenyloctahydro-1H-4,12a-Etheno-8,12-Methanopyrrolo[3’,4’:3,4]Pyrido[1,2-a] [1,5]Diazocine-1,3,5(4H)-Trione

We performed screening of nootropic properties of 10 new derivatives of quinolizidine alkaloid (-)-cytisine. Compounds with β-endo stereochemistry were more active than α-endo-isomers. Under stress conditions (3aR,4S,8S,12R,12aS,12bR)-10-methyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3’,4’:3,4]pyrido[1,2-a] [1,5]diazocine-1,3,5(4H)-trione enhanced memory and had a positive effect on cognitive functions of rats. According to molecular docking data, the nootropic activity of the compound can be associated with its affinity for the glutamate-binding subunits GluK1 and GluR2 of the kainate and AMPA receptor, respectively.

Hepatoprotective and Choleretic Properties of Levopimaric Acid Derivatives

The hepatoprotective and choleretic activities of three levopimaric acid derivatives were studied experimentally using a CCl4-induced acute hepatitis model in rats. It was established that all investigated levopimaric acid derivatives tended to increase bile secretion whereas (5R,9R,13S,18S)-20-isopropyl-5,9-dimethyl-17-{[(4-methylphenyl)sulfonyl]imino}-14-oxopentacyclo[10.6.2.01, 10.04, 9.013, 18]eicosa-15,19-diene-5-carboxylic acid (I) and dimethyl (4bS,8R)-2-isopropyl-3′-4b,8-trimethyl-2′,4′-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10a-ethanophenanthrene-11,5′-[1,3]thiazolidine]-8,12-dicarboxylate (II) reduced transaminase enzyme levels in blood serum.

Composition and Pharmacological Activity of Neutral Lipids from Rhizomes with Roots of the Introduced Plants Helleborus abchasicus and H. caucasicus

The compositions of neutral lipids (NL) and fatty acids (FA) from subterranean parts of the introduced plants Helleborus abchasicus and H. caucasicus (Ranunculaceae) were established and compared with those of the wild species. The FA from diacyl- and triacylglycerides and free FA from these introduced species had elevated contents of unsaturated acids because of 18:2. The lipid-soluble NL constituents included 10 identified sterols, the major ones of which were cholesterol, sitosterol, and lanosterol. NL from H. abchasicus (introduced and wild) and H. caucasicus (wild) exhibited pronounced anti-inflammatory activity at the level of Voltaren and moderate wound-healing activity.

Choleretic activity of 2-demethoxycarbonyl-2-ethoxycarbonyl-11-deoxymisoprostol on the model of CCl4-induced hepatitis.

Therapeutic administration of 11-deoxymisoprostol had a hepatoprotective effect, which manifested in a decrease in the content of alanine transaminase and aspartate transaminase in blood plasma, and produced a choleretic effect in rats with CCl4-induced toxic hepatitis.