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23RESEARCH RESULT
II А У 4 IT Ы И РЕЗУЛЬТАТ
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
Rus.
UDC: 616.12-008.313:615.222:615.015]-092.9
Saida K. Bogus1 Konstantin F. Suzdalev2 A.V. Uvarov1
Pavel A. Galenko-Yaroshevsky1 P.M. Vasil'ev4 Dmitry V. Vinakov3 Natalia V. Kiseleva1 A.N. Kochetkov3 A.V. Kiselev5
DOI: 10.18413/2313-8971-2017-3-4-26-34
ANTI-INFLAMMATORY AND ANALGESIC PROPERTIES OF SS-68 INDOLE DERIVATIVE
1Kuban State Medical University, 2Southern Federal University, Belgorod State National Research University, Volgograd State Medical University, 5Krasnodar branch of S.N. Fyodorov Eye Microsurgery Complex Corresponding author, 1e-mail: [email protected]
Abstract
The experiments with rats show that when administered intravenously (5 mg/kg) and intragastrically (5, 10, 15 and 20 mg/kg), SS-68 compound exerts an antiinflammatory effect (AIE) on models of acute inflammation, caused by carrageenin and serotonin, and exerts no AIE in case of edema induced by complete Freund's adjuvant (CFA) and histamine, except for intragastric administration at a dose of 20 mg/kg.
By its antiphlogogenic effect in case of carrageenin and serotonin edemas, SS-68 is comparable to diclofenac (5, 10 and 15 mg/kg intragastrically) and indomethacin (10 mg kg intragastriccally), and exceeds piroxicam (20 mg/kg intragastrically). By reference to its therapeutic index (TI), in the first case SS-68 exceeds diclofenac, indomethacin and piroxicam 2.2, 15.6 and 5.6 times, and in the second case it exceeds them 1.8, 12.8 and 4.4 times, respectively.
In the mouse acetic writhing test, which reflects the predominant effect on k (kappa)-opioid receptors, SS-68 when administered intraperitoneally at doses of 0.03, 0.06 and 0.12 mg/kg causes a dose-dependent decrease in the number of writhes by 40.0, 69.0 and 80.3%, respectively. Butorphanol, used for comparison in doses of 0.03, 0.12, 0.24, 0.48 and 0.96 mg/kg, exerts a dose-dependent analgesic effect (AE), with the number of writhes being 41.5, 52.4, 65.3, 71.1 and 80.6%, respectively. By its analgesic activity and TI, SS-68 exceeds butorphanol 1.9 and 2.7 times, respectively. Based on the results of the docking of affinity indicators for K1-opioid receptors of SS-68, butorphanol (agonist-antagonist), as well as U-50488 compounds (selective agonist), it was established that, in accordance with the calculated values of the binding constant, the affinity in relation to SS-68 was 4.53 times higher than for butorphanol, and when compared with U-50488 it was 2.84 times lower. The suggestion is that AE of SS-68, like that of butorphanol, can be linked with both affinity for K1-receptors and for other types of opioid receptors (mu, delta) and k-receptor subtypes (k2 or k3).
RESEARCH RESULT
II А У 4 IT Ы И РЕЗУЛЬТАТ
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
Keywords: SS-68indole derivative, diclofenac sodium, indomethacin, piroxicam, anti-inflammatory effect, carrageenin, serotonin, histamine, complete Freund's adjuvant, analgesic effect, kappa opioid receptors
Introduction
Earlier, we have shown that SS-68 indole derivative has a high antiarrhythmic (in case of heart rhythm disorders of peripheral and central genesis) and anti-ischemic (antianginal) effect [1]. Besides, it is known that indole derivatives, in particular indomethacin and etodolac [2], have pronounced anti-inflammatory and analgesic properties.
According to [3], of all opioid receptor subtypes, the K(kappa)-opioid receptor system takes the most significant part in developing the aforementioned pharmacological effects of many substances, and K-receptor agonists can potentially become promising in terms of being used as a base for creating new medications with antiarrhythmic, antianginal, anti-inflammatory, analgesic and other effects.
In view of the foregoing, it was of interest to study the anti-inflammatory and analgesic (realized through the impact on K-opioid receptors) effect of SS-68.
The Goal was to evaluate the antiinflammatory and analgesic effect of SS-68.
Materials and Methods
The SS-68 compound was synthesized at the Department of Natural and High Molecular Compounds at the Southern Federal University (Rostov-on-Don, Russia).
The experiments were carried out on 87 white non-linear male mice and 302 male rats weighing 22-24 g and 210-230 g, respectively. The animals were kept in the standard conditions in a vivarium in accordance with GOST R 50258-92.
Studies of anti-inflammatory and analgesic effects were carried out in compliance with the "The Guidelines for Conducting Pre-clinical Studies of Medications" [4].
To study the effect of SS-68 on exudative inflammation, there were used the models of inflammation caused by carrageenin [5], serotonin, histamine and complete Freund's adjuvant [4]. Phlogogenic substances (made by "Sigma") - carrageenin (1%), serotonin (0.1%), histamine hydrochloride (2 mM) and CFA (0.1
ml) were injected subplantarly into the right hind paw of the rats. The compound SS-68, water-based for injection, was injected intravenously (iv) into the vein of the tail and intragastrically (IG) once for histamine and serotonin-induced edemas and twice in case of edemas caused by carrageenin and CFA. Diclofenac sodium, indomethacin and piroxicam (tablets crushed to homogeneous mass in Tween-80), used as reference preparations, were injected ig once through the probe 1 hour before phlogogens.
The volume of the paws (the right one and the left intact one) was measured oncometrically using a plethysmometer ("UgoBasile", Italy) 4 and 24 hours after carrageenin and CFA administration, 30 and 45 minutes after histamine and serotonin administration, respectively.
For assessing the inflammatory response of the paw, the following formula (1) was used:
Vt-Vo
I = X 100% , (1)
Vo
where I - is an increase in paw volume (%); Vt - paw volume after injection of phlogogen (ml); and Vo - paw volume before phlogogone administration (ml).
The therapeutic effect of SS-68 and reference preparations was evaluated in comparison with the control; the calculations were made by using the formula (2):
100% - ^ e : ^ c X 100% , (2)
Vo Vo
where e - are experimental animals, c - are control animals.
In addition, the antiphlogogenic affect of substances was assessed by average effective doses (ED50) and a range of therapeutic effect -the therapeutic index (TI = LD50 / ED50).
The analgesic effect was studied using mouse acetic writhing test. The chosen test is intended to study the acute visceral and deep
RESEARCH RESULT
somatic pain [6, 7].
The SS-68 compound and butorphanol tartrate (JSC Moscow Pharmaceutical Factory, Russia), taken for comparison, both water-based for injections, were administered to the animals once intraperitoneally (ip) to the right lower third of the abdomen in doses ranging from 0.03 to 0.12 mg/kg and from 0.03 to 0.96 mg kg, respectively, 5 minutes before ip (on the left side) injection of 0.6% acetic acid solution (0.1 ml/10 g of body weight) [6]. The degree of analgesic effect (A) of substances was expressed as a percentage, using the following formula (3):
Nc-Ne
A = X 100%, (3)
Nc
where Nc - is the number of writhes in the control group of animals, Ne - in the experimental group.
In addition, the analgesic effect was evaluated by ED50 and TI.
Besides, the K1-opioid receptor SS-68, butorphanol, a partial agonist of the k1 receptors, and U-50488, a highly selective k1 receptor agonist, were docked into a specific binding site. The construction of 10 conformations of each compound was carried out in Marvin Sketch 17.1.23 program [8]. These conformations were optimized in M0PAC2016 [9] and the best one with minimal energy was selected. The docking of a human K1-opioid receptor (PDB code 4DJH) into an X-ray diffraction dimer model [10] was performed using AutoDock Vina 1.1.1 [11] (each compound was docked 5 times into each of the two dimer sites), along with calculating the minimum docking energy AE. The ensemble docking procedure is described in detail in [12].
The calculation for the docking energy AE of the binding constants K was carried out using the formula (4):
K = e-hE/RT , (4)
where R - is gas constant equal to 8.314
J/mol; T - temperature, the standard value in docking is 300 oK.
Statistical processing of the data obtained in graded and alternative forms was carried out by means of computer software developed at the Department of Pharmacology of Kuban State Medical University of the Ministry of Healthcare of Russia.
Results and Discussion
SS-68 compound administered iv to rats at a dose of 5 mg/kg caused a marked inhibition of exudative inflammation triggered by phlogogens carrageenin and serotonin, while inhibition of edema compared with the control group was 71.4 and 77.8 %, respectively (Table 1). No inhibition of edema was observed when administering SS-68 in the indicated dose and via the above channel in cases of inflammatory process caused by CFA and histamine (Table 1).
In cases of administering ig SS-68 and diclofenac in doses of 5, 10 and 15 mg/kg, the inhibition of carrageenin and serotonin edema was 36.2 and 27.5, 59.0 and 52.8, 75.2 and 79.2 for the former substance, and 24.5 and 28.4, 52.4 and 54.3, 67.8 and 72.5% for the latter substance, respectively, i.e., in terms of the antiexudative effects of SS-68 and diclofenac in presence of marked phlogogens, they were close. It was of interest to compare the antiphlogogenic effect of SS-68 under the accepted experimental conditions with that of indomethacin and pyroxicam in doses of 10 and 20 mg/kg, which, according to our data and literature data [13], corresponds to ED50. It was found that with carrageenin and serotonin inflammation, indomethacin and piroxicam caused inhibition of edema by 45.4 and 97.1, 54.8 and 40.6%, respectively (Table 1), that is, the antiphlogogenic effect of these drugs was close to that SS-68. The exception was the antiexudative effect of indomethacin in serotonin edema, which was more significant than that of SS-68, as well as of diclofenac and piroxicam.
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
RESEARCH RESULT
II A У Ч IT Ы И РЕЗУЛЬТАТ
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
Table 1
The impact of SS-68, diclofenac, indomethacin and piroxicam on the development of acute exudative edema caused by carrageenin, CFA, serotonin and histamine in
rats (M ± m)
Inflammatio n initiator
Substance No of Dose, Route Edema increase, inhibit %
under study animals mg/kg %
Control 8 59.7 ± 6.5
SS-68 8 5 iv 16.9 ± 3.6*** 71.7
10 5 ig 38.1 ± 3.1** 36.2
10 10 ig 24.5 ± 4.1*** 59.0
10 15 ig 14.8 ± 3.8*** 75.2
Diclofenac 9 5 ig 45.1 ± 2.1* 24.5
10 10 ig 28.4 ± 4.1*** 52.4
10 15 ig 19.2 ± 3.5*** 67.8
Indomethacin 8 10 ig 32.6 ± 5.2** 45.4
Piroxicam 8 20 ig 27.0 ± 8.6*** 54.8
Control 8 78.8 ± 3.4
SS-68 8 5 iv 17.5 ± 6.0*** 77.8
10 5 ig 57.1 ± 4.7** 27.5
10 10 ig 37.2 ± 4.3*** 52.8
10 15 ig 16.4 ± 3.8*** 79.2
Diclofenac 10 5 ig 56.4 ± 4.8** 28.4
9 10 ig 36.0 ± 5.6*** 54.3
10 15 ig 21.7 ± 4.2*** 72.5
Indomethacin 8 10 ig 2.3 ± 0.9*** 97.1
Piroxicam 8 20 ig 46.8 ± 5.8** 40.6
Control 8 147.0 ± 9.0
SS-68 8 5 iv 154.9 ± 8.0 -5.4
8 10 ig 138.7 ± 7.6 5.6
10 20 ig 105.0 ± 8.2** 28.6
Diclofenac 10 10 ig 98.6 ± 6.3*** 32.7
Indomethacin 8 10 ig 67.7 ± 5.0*** 53.9
Piroxicam 8 20 ig 112.6 ± 17.6 23.4
Control 8 70.0 ± 9.7
SS-68 8 5 iv 54.1 ± 9.2 22.7
10 10 ig 68.3 ± 7.9 2.4
10 20 ig 37.4 ± 4.5** 46.6
Diclofenac 8 10 ig 29.0 ± 3.8*** 58.6
Indomethacin 8 10 ig 40.3 ± 8.6* 42.4
Piroxicam 8 20 ig 60.5 ± 4.7 13.6
Carrageenin
Serotonin
CFA
Histamine
Note: *р< 0.05, ** p< 0.01,***p< 0.001 compared with control
To assess the antiexudative effect of SS-68 and reference preparations, we compared their ED50 (calculated for SS-68 and diclofenac and borrowed from literature sources for piroxicam [13]) and TI. It turned out that by activity (ED50) SS-68, diclofenac and indomethacin are
almost comparable. As for piroxicam, SS-68 was 2.4 times more significant by this indicator in relation to it. By their TI in the case of carrageenin and serotonin inflammation, SS-68 exceeded diclofenac, indomethacin and piroxicam 2.2, 15.6 and 5.1 times in the former
RESEARCH RESULT
НАУЧИ Ы Й РЕЗУЛЬТАТ
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
case, and 1.8, 12.8 and 4.4 times in the latter
case, respectively (Table 2).
Table 2
Acute toxicity, anti-inflammatory effect and TI of SS-68, on carrageenan and serotonin models of exudative inflammation in rats
Exudative inflammation models
Substance LD501, mg/kg
carrageenan
ED50, mg/kg
TI
serotonin
ED50,
TI
SS-68 608.0 8.3 73.3 9.S 64.0
Diclofenac 3S0.02 l0.4 33.7 9.б 36.S
Indomethacin 47.03 l0.0 4.7 9.4 S.0
(26.0 ' 85.0)
Piroxicam 290.04 20.04 14.S 20 14.S
(193.0 ' 435.0) (13.0 ' 32.0)
For mice via ig administration 2Neugodnova, O.P. et al. [14]. 3 Tsarichenko, G.V., Gan ina, G.A. [15]. 4Sigidin, Ya.A. et al. [13]. Note: In brackets is confident limit when p=0.05.
With CFA-and histamine-induced edema, SS-68 (iv 5 mg/kg and/or 10 mg/kg) and piroxicam (ig 20 mg kg) showed no statistically significant anti-inflammatory effect, whereas SS-68 (ig 20 mg/kg), diclofenac (ig 10 mg/kg) and indomethacin (ig 10 mg/kg) inhibited the edema induced by the former phlogogen by 28.6, 32.7 and 53.9%, by the latter - by 46.6, 58.6 and 42.4%, respectively.
Our data on the anti-inflammatory effect of SS-68 in the selected models of edema reflecting various pathogenetic mechanisms of acute exudative inflammation (carrageenan edema simulates the prostaglandin phase of inflammation completed by affecting cyclooxygenase; serotonin and histamine edemas simulate the release of the marked biogenic amines increasing vascular permeability from mast cells; CFA-induced edema coincides with the initial phase of inflammation involving cytokines, in particular IL-1, IL-2, IL-6, IL-8, TNF-a, IFN-y, as well as leukotrienes accumulated at that stage of arachidonic acid metabolism, which is realized via the 5-lipoxygenase pathway [16, 17]) to a
certain extent attest to the "universal" mechanism of anti-inflammatory effect of SS-68.
Thus, SS-68 with iv and ig administration can exert an anti-inflammatory (dose-dependent in the latter administration route) effect on models of acute carrageenin- and serotonin-induced inflammation, and exerts no anti-inflammatory effect with CFA- and histamine-induced edema, except cases of ig administration at a dose of 20 mg/kg.
According to antiphlogogenic activity in carrageenan and serotonin edema, SS-68 is comparable with diclofenac and indomethacin and exceeds piroxicam, and by TI it exceeds all the reference preparations.
In the mouse acetic writhing test, which reflects the predominant effect on к-receptors, the number of writhes in the control group of animals was 29.4 on average. The SS-68 compound at doses of 0.03, 0.06 and 0.12 mg/kg caused a dose-dependent decrease in the number of writhes by 40.0, 69.0 and 80.3%, respectively (Table 3).
RESEARCH RESULT
II A У Ч IT Ы Й РЕЗУЛЬТАТ
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
Table 3
Analgesic effect of SS-68 and butorphanol with ip administration in mouse acetic writhing test (M ± m)
Substance No of animals Dose, mg/kg Analgesic effect number of writhes in relation to control, %
Control 12 29.4 ± 2.8 -
10 0.03 17.6 ± 2.6* 40.0
SS-68 10 0.06 9.1 ± 1.2** 69.0
10 0.12 5.8 ± 1.1** 80.3
10 0.03 17.2 ± 2.4* 41.5
8 0.12 14.0 ± 1.3** 52.4
Butorphanol 9 0.24 10.2 ± 1.5** 65.3
8 0.48 8.5 ± 1.6** 71.1
10 0.96 5.7 ± 1.2** 80.6
Note: * р< 0,01, ** p< 0,001compared with control
Butorphanol, used for comparison under the experimental conditions, at doses of 0.03, 0.12, 0.24, 0.48 and 0.96 mg/kg had a dose-dependent analgesic effect, with the number of writhes in comparison with that in the control group being 41.5, 52.4, 65.3, 71.1 and 80.6%, respectively (Table 3). The calculation of ED50
and TI of SS-68 and butorphanol showed that for the former their values are 0.038 mg/kg and 7276.3, and for the latter - 0.072 mg/kg and 2666.7, that is, by its analgesic effect and TI, SS-68 exceeds butorphanol 1.9 and 2.7 times, respectively (Table 4).
Table 4
Acute toxicity, analgesic effect and TI of SS-68 and butorphanol when administered ip in mouse acetic writhing test
Substance LD50, mg/kg ED50, mg/kg Analgesic effect relative TI relative
SS-68 276.5 0.038 1.9 7276.3 2.7
Butorphanol 1 л • • 192.01 0.072 1 2666.7 1
To confirm the agonistic effect of SS-68 on K1-receptors, we compared the affinity values of SS-68, butorphanol, and U-50488 compound for these receptors, calculated basing on the docking results. It was found that, in
accordance with the target value of the binding constant, the affinity of SS-68 for the K1-opioid receptors was 4.53 higher than that of butorphanol, and 2.84 times lower than that of U-50488 (Table 5).
Table 5
Results of docking SS-68, butorphanol and U-50488 substance into specific binding site
of Ki-opioid receptor
Substance Docking energy AE, Binding constant K, nM _kcal/mol___
SS-68 -8.60 538.1
Butorphanol -7.70 2437.3
U-50488 -9.20 196.5
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It should be noted that U-50488 is more toxic than SS-68: when administered ip to mice, the LD50 of the former being 25 mg/kg [19], whereas for the latter - 276.5 mg/kg.
Thus, SS-68 has an analgesic effect, realized through the peripheral level of establishing pain sensitivity through agonistic action on K1-receptors. It is possible that the analgesic effect of SS-68, like that of butorphanol, can be linked to affinity for k1-receptors, other types of opioid receptors (mu, delta) and for K-receptor subtypes (k2 or k3). To identify the possible involvement of certain opioid receptors in the mechanism of analgesic action of SS-68, additional in-depth studies are needed, which will make it possible to classify SS-68 as either selective or non-selective k-receptor agonist.
Acknowledgements
The SS-68 compound was synthesized and developed within the grant project from
The Southern Federal University BHrp -07/2017-11. The individuality and structure of the compound were monitored by thin-layer chromatography and by NMR and IR spectroscopy. NMR spectra were recorded at the Educational and Scientific Laboratory of Resonance Spectroscopy of the Department of Chemistry of Natural and High-Molecular Compounds of The Southern Federal University. IR spectra were recorded at the Molecular Spectroscopy Center for Collective Use of The Southern Federal University.
Conflicts of Interest
The authors have no conflict of interest to declare.
References
1. Bogus SK., Galenko-Yaroshevskiy PA, Dukhanin AS, Shimanovskiy NL. Effect of indole derivatives SS-68 having antiarrhythmic and antianginal properties on a 1-, P 1-and P 2 adrenergic receptors. New technologies. [Novye Tekhnologii]. 2012.4:232 - 235. (in Russian) [Full text]
2. Mashkovskiy MD. (2016). Lekarstvennye sredstva. [Medications]. Moscow: Novaya Volna. Print. (in Russian)
3. Chen Y, Chen C, Liu-Chen LY.
Dynorphin Peptides Differentially Regulate the Human Kappa Opioid Receptor. Life Sci. 2007;80(15):1439-1448. doi.org/10.1016/j.lfs.2007.01.018 [Abstract!
4. Mironov AN. et al. (2012). Rukovodstvo po provedeniyu doklinicheskix issledovanij lekar-stvennyx sredstv. [A Guide to Preclinical Research of Medications]. Moscow. (in Russian)
5. Winter CA, Risley EA, Nuss GW. Carrageenin-induced Edema in Hind Paw of the Rat as an Assay for Anti-inflammatory Drugs. ProcSocExpBiol Med. 1962;111:544-547. [PubMed]
6. Spasov AA., Grechko OYu., Shtaryova DM., Anisimova VA. Analgesic Properties of Morpholinoethylimidazobenzimidazole Derivative RU-1205. Russian Journal of Experimental and Clinical Pharmacology [Eksperimentalnaya i Klinicheskaya Farmakologiya]. 2013;76(9):15-18. (in Russian) [eLIBRARY]
7. Krylova, S. G., Zorikov, P. S., Zueva, E. P., Razina, T. G., Amosova, E. N., Rybalkina, O. Yu. (2014). Experimental study of the analgesic activity of aconitum Kuznezoffi reichenb. Pacific Medical Journal Tikhookeanskiy Medicinskiy Zhurnal. 2014;2:38-40. (in Russian) [eLIBRARY]
8. MarvinSketch, ChemAxonKft. (2017, June 19). Retrieved from http://www.chemaxon.com/products/marvin/m arvinsketch/
9. MOPAC, Stewart Computational Chemistry. (2017, June 19). Retrieved from http://openmopac.net.
10. Wu H, Wacker D, Mileni M, Katritch V, Won HG, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. (2010). Structure of the Human k-opioid Receptor in Complex with JDTic. Nature. 2010;485:327-332. doi: 10.1016/j.ejmech.2014.12.016. [PubMed]
11. Trott O, Olson AJ. AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization and Multithreading. J. Comp. Chem. 2010;31(2):455-461. doi: 10.1002/jcc.21334. [PubMed]
12. Vasilyev PM, Spasov AA, Kochetkov
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
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II A y M II M Ü PE3yjIbTAT
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
AN, Vorfolomeeva VV, Yanalieva LR. (2016). Konsensusnyy podkhod k poisku insilico protivodiabeticheskikh soedineniy. [A Consensus Approach to Searching for insilico Antidiabetic Remedies]. In Mishen-orientirovannyy Poisk Antidiabeticheskikh Sredstv (pp. 126-181). Volgograd: Publishing House of Volgograd State Medical University. (in Russian) [eLIBRARY]
13. Sigidin YaA, Shvarts GYa, Arzamastsev AP, Liberman SS. (1988). Lekarstvennaya terapiya vospalitelnogo protsessa: eksperimentalnaya i klinicheskaya farmakologiya protivovospalitelnykh preparatov. [Drug Therapy of the Inflammatory Process: Experimental and Clinical Pharmacology of Anti-inflammatory Drugs]. M.: Medicina. Print. (in Russian)
14. Neugodnova OP, Tsarichenko GV, Ryndina AE, et al. Toxicological Evaluation of Voltaren. Pharmacol. i Toxicol. 1986; 1:123. (in Russian)
15. Tsarichenko GV, Ganina GA. Toxicity of Indopan. Pharmacol. i Toxicol. 1986;2:117. (in Russian)
16. Shvarts G. (2004). Sovremennye nesteroidnye protivovospalitelnye preparaty. [Modern Non-steroidal Anti-inflammatory Drugs]. M: Reapharm. Print. (in Russian) [eLIBRARY]
17. Galenko-Yaroshevskiy VP, Galka VV, Varlashkina IA, Kovaleva VL. Influence of Enoxifol on Acute Inflammation. Byulleten eksperimentalnoy biologii i meditsiny. 2007;3:151-152.(in Russian)
18. Anisimova, V.A. et al. (2011). Patent of RF No. 2 412 187 C1 of 29.07.2009. Salts pf 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[ 1,2-a]benzimidazole and Salts of 9-aminoethyl-substituted 2-(4-fluorophenyl)imidazo[ 1,2- a]benzimidazole with Analgesic Effect. Bul. №5. (in Russian)
19. Kuzeff, R.M., Topashka-Ancheva, M.N., Mecheva, R.P. (2004). Inhibition of (-)-trans-(1S,2S)-U50488 Hydrochloride by its Enantiomer in White Mice -- a Placebo-controlled, Randomized study. Forsch. Komplementarmed. Klass. Naturheilkd. 2004;11(3):144-149. doi: 10.1159/000079443 [PubMed]
Author Contributors
Saida K. Bogus, PhD in Medicine, Assistant Professor, Department of Pharmacology, Kuban State Medical University of the Russian Ministry of Healthcare, e-mail: [email protected] Contributor to all parts of the article.
Konstantin F. Suzdalev, PhD in
Chemistry, Associate Professor, Department of Chemistry of Natural and High-molecular Compounds, Faculty of Chemistry, Southern Federal University, e-mail:
[email protected]. Synthesis of SS-68 compound.
Aleksandr V. Uvarov, PhD in Medicine, Associate Professor, Department of Pharmacology, Kuban State Medical University of the Russian Ministry of Healthcare, e-mail: [email protected] Contributed to the study of reference anti-inflammatory drugs.
Pavel A. Galenko-Yaroshevsky, Doctor of Medical Science, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Pharmacology, Kuban State Medical University of the Russian Ministry of Healthcare, e-mail: [email protected] Research project supervising.
Pavel M. Vasil'ev, Doctor of Biology, Professor, Department of Pharmacology and Bioinformatics, Volgograd State Medical University of the Russian Ministry of Healthcare, Senior researcher, e-mail: [email protected]. ORCID: 0000-0002-81885052. Supervised and contributed to molecular docking study.
Dmitryy V. Vinakov, post-graduate student, Department of Pharmacology, Institute of Medicine, Belgorod State National Research University. Contributed to the study of anti-inflammatory effect.
Nina V. Kiseleva, 6-year student, Faculty of General Medicine, Kuban State Medical University of the Russian Ministry of Healthcare, e-mail: [email protected] Contributed to the study of anti-inflammatory effect.
Andrey N. Kochetkov, research technician, Department of Pharmacology and Bioinformatics, Volgograd State Medical University of the Russian Ministry of
RESEARCH RESULT
H A y 3 IT M ii PE3yjIbTAT
Bogus S.K., Suzdalev K.F., Uvarov A.V., Galenko-Yaroshevsky P.A., Vasil'ev P.M., Vinakov D.V., Kiseleva N.V., Kochetkov A.N., Kiselev A.V. Anti-inflammatory and analgesic propertiesof SS-68 indole derivative. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):26-34.
Healthcare, e-mail: [email protected] Contributed to molecular docking study.
Aleksandr V. Kiselev, PhD in Medicine, Head of the Laboratory for Tissue Preservation "Eye Bank", Krasnodar branch of S.N. Fyodorov Eye Microsurgery Complex of the Russian Ministry of Healthcare, e-mail: [email protected] Contributed to the study of anti-inflammatory effect.
Received: October, 27, 2017 Accepted: November, 30, 2017 Available online: December, 30, 2017
