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Azamatov Azizbek Azamat o'gli, Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent, Junior scientist Tursunkhodzhaeva Firuza Muratovna, candidate of Biological Sciences, Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent, Senior scientist E-mail: fim40438@gmail.com Rejepov Jimadulla, candidatye of Medical Sciences, Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent, Leading scientist Maksudova Alloma Nizamovna, candidate of Biological Sciences, Public Health Ministry, RUz, dotsent Tashkent Pharmaceutical Institute
PSYCHOTROPIC ACTIVITY OF CYTISINE N-BENZOYL DERIVATIVES
Abstract: Psychotropic activity in open field conditions, antihypoxic activity on the model of normobaric hypoxia with hypercapnia, antinarcotic (against sodium ethaminal), and anticonvulsant activity (pentylenetetrazole) of N-benzoyl derivatives of cytisine were explored. It has been established that the studied substances have a psy-chostimulating effect, increases motor activity, orientation and research behavior, brain resistance to hypoxia, and have antinarcotic and anticonvulsant effects.
Keywords: Cytisine derivatives, psychotropic activity, antihypoxic activity, convulsions, anesthesia, motor and research activity.
Introduction and methods of research: CNS stimu- stands and surveyed holes. The mean values of the param-lants are widely used in a complex treatment of neurodegen- eters for the group, their standard deviations and confidence erative disorders, intoxication with alcohol, drugs and other intervals were calculated.
psychoactive substances. Cytisine derivatives have neurophar- Antihypoxic activity was studied on white mice with the
macological activity proved in many studies [1-5]. same weight of 21-22 grams on the model of normobaric hy-
The purpose of this work is to study psychotropic activity poxia with hypercapnia. The animals were placed by twos in of a series of N-benzoyl derivatives of cytisine. hermetically sealed 500 cm3 cans. The survival time of mice
The effect of the testing compounds on the orienting- under hypoxic conditions was recorded and the percentage of investigation behavior was carried out in experiments on increase in the survival time relatively to the control group was white male mice weighing 18-22 grams in open field 40 x calculated. Each dose was tested on 10 animals. x 40 cm divided into squares of 10 x 10 cm with 16 round The analeptic effect of the tested substances was assessed
holes of diameter 4 cm. The investigated substances were by their antagonism with sodium ethaminal effect. The so-injected to mice subcutaneously at doses of 0.1, 0.5, 1.0, dium ethaminal was administered intraperitoneally at a dose and 5 mg/kg. Each dose of drug was tested on 10 mice. The of 50 mg/kg in 30 minutes after subcutaneous injection of control group of mice under the same experimental condi- the tested substances. The duration of anesthesia (mice lateral tions was administered a sterile isotonic NaCl solution. In position) was recorded.
30 minutes after injection the observation of experimental Convulsions were induced by subcutaneous administra-
mice behavior were held for 2 minutes, including number tion of pentylenetetrazole at a dose of 80 mg/kg. The tested of horizontal displacements in intersected squares, vertical substances were administered subcutaneously in 30 minutes
before the application of pentylenetetrazol Time of trem- Piracetam-Darnitsa (400 mg/kg) preparation was used
orogenic - convulsive action onset, its duration, and time of as a comparative drug in all experiments. The obtained data animals death was recorded. were processed by Student [6].
Table 1.- Effects of cytisine N-benzoyl derivatives on orientation-exploratory behavior
of mice in open field (n=10)
No. Investigated substances Dose, mg/kg s/c Horizontal movies Vertical stands Holes survey
1. Control group (NaCl solution) 0.2 11 ± 3.8 6.4 ± 2.1
2. Pyracetam 400 15.4 ± 4.1 6 ± 2.0 19.2 ± 4.4
3. Cytisine 0.1 16 ± 3.6 8 ± 1.9 27.6 ± 3.7
0.5 16.2 ± 3.5 8.5 ± 1.6 19.8 ± 1.9
1.0 16.6 ± 3.7 6.8 ± 1.3 21.6 ± 2.4
2.0 18.8 ± 4.2 5 ± 1.2 22.5 ± 2.5
4. N-(2-oxybenzoyl) cytisine hydrochloride 0.1 10.4 ± 3.4 3.6 ± 1.3 11.8 ± 3.8
0.5 18.2 ± 4.2 10.8 ± 2.4 12.6 ± 3.5
1.0 17.4 ± 5.1 8.2 ± 1.9 12 ± 3.4
5.0 9.6 ± 3.2 4.7 ± 1.2 9.4 ± 2.9
5. N-(3,4-methylenedioxybenzo -yl) cytisine hydrochloride 0.1 18.4 ± 4.5 7 ± 1.6 30.2 ± 6.2
0.5 17.5 ± 4.3 5.5 ± 1.3 29.4 ± 5.5
1.0 16.2 ± 3.8 5.2 ± 1.2 30.6 ± 6.5
5.0 12.6 ± 3.6 4.6 ± 1.1 14.4 ± 3.2
6. N-(2-bromo -3-oxy-4-me-thoxybenzoyl) cytisine hydrochloride 0.1 15.2 ± 4.0 6.8 ± 1.4 27.6 ± 4.1
0.5 18.4 ± 4.9 8 ± 1.6 26.2 ± 4.8
1.0 16.6 ± 3.7 8.2 ± 1.2 34.7 ± 4.3
5.0 15.6 ± 3.3 5.6 ± 1.3 22.6 ± 3.9
7. N-(3,4-dimethoxy-6-bromb -enzoyl) cytisine hydrochloride 0.1 14.2 ± 3.5 7.4 ± 1.2 30.2 ± 3.5
0.5 17.6 ± 4.4 6.2 ± 1.4 31 ± 3.6
1.0 16.4 ± 3.7 9 ± 2.0 34.6 ± 4.0
5.0 13.8 ± 2.9 5.7 ± 1.8 30.5 ± 4.1
Results of the study and discussion. The experimental data showed that the studied N-benzoyl derivatives of cytisine possess high psychostimulating activity. All studied substances significantly increased the motor activity and orienting-exploratory behavior of the experimental mice in the open field (Table 1), increased the survival time of mice under conditions of normobaric hypoxia with hypercapnia (Table 2), showed pronounced antagonism, analeptic effect in narcosis caused by sodium ethaminal (Table 3), and anti-
convulsant effect on the convulsions caused by subcutaneous administration of pentylenetetrazole (Table 4).
The intensity of the stimulating effects depended on the dose of the investigated substances. Overdose of optimal doses reverse the stimulating effect and lead to inhibition of animal's activity.
This effect manifested most clearly in the open field test which is characteristic for substances having stimulating action.
No. Investigated substances Dose, mg/kg s/c Surviving time, min. Reserve time increasing,%
1 2 3 4 5
1. Control group (NaCl solution) 0.2 17.8 ± 0.56 -
2. Pyracetam 400 17.4 ± 0.75 19.1**
3. Cytisine 0.1 21 ± 1.2 19.9**
0.5 16.8 ± 0.8 -5.6
1.0 16.2 ± 0.95 -8.9
2.0 18.4 ± 0.86 9.3
4. N-(2-oxybenzoyl) cytisine hydrochloride 0.1 20.8 ± 0.8 16.8**
0.5 23.8 ± 1.1 33.7*
Table 2.- Time of mice survival in normobaric hypoxia with hypercapnia (n = 10)
1 2 3 4 5
4. N-(2-oxybenzoyl) cytisine hydrochloride 1.0 21 ± 1.1 17.9 **
5.0 18.8 ± 0.7 5.6
5. N-(3,4-methylenedioxybenzoyl) cytisine hydrochloride 0.1 21.4 ± 0.96 28.9 *
0.5 18.2 ± 0.67 9.6
1.0 20 ± 0.75 20.4 **
5.0 16.8 ± 0.62 1.2
6. N-(2-bromo-3-oxy-4-methoxyben-zoyl) cytisine hydrochloride 0.1 22.4 ± 0.92 30.2 *
0.5 21.8 ± 0.95 26.7 **
1.0 17.6 ± 0.74 2.3
5.0 18.5 ± 0.85 7.5
7. N-(3,4-dimethoxy-6-brombenzoyl) cytisine hydrochloride 0.1 17.8 ± 0.82 -3.2
0.5 21 ± 1.0 14.1 **
1.0 20.6 ± 1.4 11.9 **
5.0 22.5 ± 1.5 22.2 *
Note: *-P < 0.01, **-P < 0.05
Table 3.- Antagonism of the investigated substances to narcotic effect of sodium ethaminal (n = 10)
No. Investigated substances Dose, mg/kg Narcotic effect duration, min.
1. Control group (sodium ethaminal i/p) 50 92.6 ± 9.4
2. Pentylenetetrazole s/c in 30 min after sodium ethaminal introduction 10 69.5 ± 7.5**
3. Caffein s/c in 30 min after sodium ethaminal introduction 10 65.2 ± 7.0**
4. Cytisine s/c in 30 min after sodium ethaminal introduction 0.1 39.8 ± 4.1*
0.5 47.4 ± 3.9*
1.0 55.2 ± 5.4*
2.0 79 ± 6.1**
5. N-(2-oxybenzoyl) cytisine hydrochloride s/c in 30 min after sodium ethaminal introduction 0.1 68 ± 5.8**
0.5 60.2 ± 7.3*
1.0 56.6 ± 6.5*
5.0 72 ± 8.4**
6. N-(3,4-methylenedioxybenzoyl) cytisine hydrochloride s/c in 30 min after sodium ethaminal introduction 0.1 52 ± 6.2*
0.5 65.4 ± 5.8**
1.0 56.2 ± 6.4*
5.0 60.7 ± 7.3*
7. N-(2-bromo-3-oxy-4-methoxybenzoyl) cytisine hydrochloride s/c in 30 min after sodium ethaminal introduction 0.1 58.4 ± 6.6*
0.5 49 ± 5.8*
1.0 47.2 ± 4.8*
5.0 68.5 ± 6.7**
8. N-(3,4-dimethoxy-6-brombenzoyl) cytisine hydrochloride s/c in 30 min after sodium ethaminal introduction 0.1 65.8 ± 7.2**
0.5 67.2 ± 6.6**
1.0 56.4 ± 7.0*
5.0 38.7 ± 3.8*
Note: *-P < 0.01, **-P < 0.05
Table 4.- Anticonvulsant effect of investigated substances (n = 10)
No. Investigated substances Dose, mg/kg Convulsions duration, min. Survival of mice, %
1 2 3 4 5
1. Control group (pentylenetetrazol) s/c 80 9.2 ± 1.2 0
2. Pyracetam s/c in 30 minutes after pentylenetetrazol 400 26.4 ± 1.4 1
0.1 16.2 ± 0.8 0
3. Cytisine s/c in 30 minutes after pentyl- 0.5 17.2 ± 1.4 1
enetetrazol 1.0 18.4 ± 1.5 3*
2.0 13 ± 0.7 0
N-(2-oxybenzoyl) cytisine hydrochloride s/c in 30 minutes after pentylene-tetrazole 0.1 10.8 ± 0.8 0
4. 0.5 14.5 ± 1.3 0
1.0 25.6 ± 1.1 1
5.0 16 ± 0.9 1
N-(3,4-methylenedioxybenzoyl) cytisine hydrochloride in 30 minutes after pentylenetetrazole 0.1 18 ± 1.2 1
5. 0.5 15.8 ± 1.3 1
1.0 14 ± 1.6 2**
5.0 16.8 ± 0.8 1
N-(2-bromo-3-oxy-4-methoxybenzoyl) cytisine hydrochloride in 30 minutes after pentylenetetrazole 0.1 20.8 ± 1.2 5*
6. 0.5 20.2 ± 0.9 3*
1.0 23 ± 1.4 3*
5.0 14 ± 0.7 2**
N-(3,4-dimethoxy-6-brombenzoyl) cytisine hydrochloride in 30 minutes after pentylenetetrazole 0.1 18.2 ± 1.3 1
7. 0.5 12.8 ± 0.7 3*
1.0 21.2 ± 1.2 2**
5.0 17.2 ± 1.5 2**
Note: *-P < 0.01, **-P < 0.05 Conclusions
1. All investigated N-benzoyl derivatives of cytisine showed high stimulating activity on the central nervous system.
2. Among studied N-benzoyl derivatives of cytisine, N-(2-bromo-3-hydroxy-4-methoxybenzoyl) cytisine provided the greatest psychostimulating effect that exceeded activity of the comparative drug.
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