2005 Bridged compounds Q 0060Synthesis and Antiarrhythmic Activity of 5-Amino-exo-3-azatricyclo[5.2.1.0 2,6 ]decan-4-one. -Products (I) show antiarrhythmic activity with ED50 values of 0.28 and 0.33 mg/kg on the aconotine and calcium chloride models. -(GORPINCHENKO, V. A.; YATSYNICH, E. A.; PETROV, D. V.; KARACHURINA, L. T.; KHISAMUTDINOVA, R. Y.; BASCHENKO, N. Z.; DOKICHEV, V. A.; TOMILOV, Y. V.; YUNUSOV, M. S.; NEFEDOV, O. M.; Khim.-Farm. Zh. 39 (2005) 6, 9-11; Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, Russia; Russ., Abstr. Eng.) -Y. Steudel 42-078

Allapinine (lappaconitine hydrobromide) is a drug for the treatment of cardiac arrhythmias, it shows IC class antiarrhythmics properties. Its action mechanism is associated with blockade of Na(+)-channels with subsequent inhibition of the depolarization rate and, consequently, of the slowing and reducing the excitability of the cardiac conduction system. At the moment, it is not established, what factors are associated with side effects of Allapinine, and therefore it seems important to study the molecular mechanisms of its action. The target genes were identified in a rat model of aconitine-induced arrhythmia using a commercial kit "Rat Neuroscience Ion Channels & Transporters RT2 Profiler PCR Array" (SABioscienses). Comparison of the expression of 84 genes in the experimental (aconitine arrhythmias/Allapinine) and control (aconitine arrhythmias/saline) animals revealed changes in the mRNA level of 18 genes. It has been shown an increase in mRNA levels of genes encoding various types of K(+)-channels (kcna6, kcnj1, kcnj4, kcnq2, kcnq4), Ca(2+)-channel (cacna 1g), vesicular acetylcholine transporter (slc 18a3). Decrease in the mRNA level was observed for genes encoding the Na(+)-channel (scn8a), K(+)-channels (kcne 1, kcns 1), membrane transporters (atp4a, slc6a9). Taken together, it appears that the effect of Allapinine on aconitine--induced arrhythmias is due to modulation of genes encoding Na(+)-, K(+)-, Ca(2+)-channels, conducting ionic currents (I(Na), I(to), I(Ks), I(K1), I(CaT)), which are involved in the formation of different phases of the action potential. The effect of the drug on the mRNA levels of genes encoding the acetylcholine and glycine transporters, suggesting the participation of these neurotransmitters in the mechanisms of anti-arrhythmic properties of the Allapinine.

The hypoglycemic activity of glycyrrhizic acid (GA, I), its trisodium (II) and sodium-dilithium salts (III), and a conjugate with L-methionine methyl ester (IV) was studied using an alloxan diabetes model after peroral administration to male Wistar rats. It was found that GA and its conjugate IV at a dose of 100 mg/kg exhibited hypoglycemic activity and reduced the blood glucose content of the animals by 35.5 and 42.6%, respectively, after 120 min. GA conjugate IV had low toxicity and hypoglycemic activity superior to those of GA and acarbose.

No abstract

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, 1 H NMR, and 13 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 13 C NMR spectrum of compound I, the signals from carbon atoms C 6 (48.43 and 48.54 ppm), C 8 (56.75 and 56.06 ppm), C 11 (62.62 and 61.52 ppm), and C 13 (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 13 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 1 and a pyramidal sulfoxide sulfur atom in the aliphatic substituent, which make possible the formation of two d-diastereomers with R*R* and R*S* centers [7].The 1 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 11 in the form of two doublets with a geminal spin -spin coupling constant of 13.3 Hz and a relative chemical shift Dd = 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 Dd value is identified as the threo isomer (Ib). Both isomers are 659