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Azamatov Azizbek Azamat o'gli, Junior Scientific Researcher of Department of Pharmacology and Toxicology of Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent E-mail: azizbek.azamatov@bk.ru Rejepov Jumadilla,
Leading Scientific Researcher of Department of Pharmacology and Toxicology of Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent Tursunkhodjaeva Firuza Muratovna, Senior Scientific Researcher of Department of Pharmacology and Toxicology of Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent Tukhtasheva Visola Farmonovna, Junior Scientific Researcher of Department of Pharmacology and Toxicology of Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent
PSYCHOTROPIC ACTIVITY OF N-(3-OXY-4-METHOXY-6-BROMOBENZOYL) AND N-(3-BROMO-4-METHOXYBENZOYL) CYTISINE HYDROCHLORIDE
Abstract: Psychotropic activity of new N-benzyl cytisine derivatives in open field conditions, their antihypoxant activity on a model of normobaric hypoxia with hypercapnia, anti-narcotic (ethaminal sodium, alcohol) and anticonvulsant activity (pentylenetetrazole) have been studied. It was established that the investigated substances have a psychostimulating effect, increase locomotor activity, exploratory behavior, the resistance of brain to hypoxia, and have antinarcotic and weak anticonvulsant action.
Keywords: cytisine derivatives, nootropic activity, antihypoxant activity, locomotor activity, convulsions, narcosis, exploratory behavior.
Introduction and research methods: Nowadays, one of The purpose of this work is to study the psychotropic
the priorities of psychopharmacology is the search for effec- activity of new N-benzyl derivatives of cytisine: tive and safe drugs for the pharmacological correction of neu- droxy-4-methoxy-6-bromobenzoyl) cytisine hydrochloride ropsychiatric disorders that, according to a multicenter study, and N-(3-bromo-4-methoxybenzoyl) cytisine hydrochloride. were diagnosed in 50-75% of the world's population [1-4]. The analyzed substances were administered subcutane-
Nootropic drugs are widely used in the complex therapy ously at doses of 0.1, 0.5, 1, and 5 mg/kg. Each dose was tested of neurological dysfunctions. They are used to treat various on 10 mice males weighing 18-22 grams. A control group of disorders of cognitive, mental functions, including mnestic, mice under the same experimental conditions were injected arising from hypoxia, intoxication, acute and chronic alco- with sterile isotonic NaCl solution.
holism, cranial brain injuries, with various degenerative brain The effect of the studied compound and the etalon
lesions, Alzheimer's disease, to enhance creative activity, es- drug (piracetam) on the exploratory behavior was per-pecially in the elderly and senile age, recovery of mental retar- formed in open field 40 x 40 cm area, drawn on 10 x 10 cm dation of children, as well as increasing the body's resistance squares with 16 round holes of diameter 4 cm. The behav-to extreme conditions [5-8]. ior of the experimental mice was observed in 30 minutes
In this regard, the search for promising new nootropic after the preliminary subcutaneous administration of the drugs is conducted among representatives of various classes preparations. During 2 minutes a number of horizontal dis-of chemical compounds, including among substances of plant placements by the number of crossed squares, the number origin [9-11]. Cytisine derivatives are promising substances of stepping on the hind legs and a number of surveyed in this area [12-16]. holes have been registered. The average values of group
parameters, standard deviations and confidence intervals were calculated.
Antihypoxant activity was studied using a model of nor-mobaric hypoxia with hypercapnia. Animals were placed by pairs in hermetically sealed cans of500 cm3. The survival time of mice under hypoxia was recorded, and the percentage increase in survival time was calculated relative to the control group. Each dose was tested on 10 animals. Experiments were performed compared with the drug piracetam.
Analeptic effect of the substances was assessed by their antagonism to sodium ethaminal and ethanol intraperito-neally at doses of 50 mg/kg and 4.8 g/kg, accordingly, in 30 minutes after the subcutaneous injection of the studied substances. The duration of lateral position was recorded. The effectiveness of the investigated substances was compared with pentylenetetrazole and caffeine.
Convulsions were caused by subcutaneous administration of pentylenetetrazole at a dose of 80 mg/kg. The studied substances were injected subcutaneously in 30 minutes before pentylenetetrazole. Tremor, the duration of convulsions and time of animal death were detected.
Table 1. - Effects of N-benzoyl derivatives of
The acute toxicity was studied at subcutaneous injection of substances. The data were processed by Student and Litch-field-Wilcoxon methods.
Results and discussion: the new N-benzyl derivatives of cytisine N- (3-hydroxy-4-methoxy-6-bromobenzoyl) and N-(3-bromo-4-methoxybenzoyl) cytisine hydrochloride showed high psychotropic activity.
The tested N-benzyl cytisine derivatives significantly increased locomotor activity and exploratory behavior of experimental mice in the open field depending on the administered dose. The introduction of N- (3-hydroxy-4-me-thoxy-6-bromobenzoyl) cytisine and N- (3-bromo-4-me-thoxybenzoyl) cytisine at a dose of 0.1-0.5-1.0 mg/kg increased locomotor activity by 60.4-104.6% and 13.9134.8%, respectively; the number ofvertical stands depending on the administered dose was 38.8-122.2% and 11.1111.1%, and the number of surveyed holes was 39.2-87.5% and 48.9-85.7%, respectively. At a dose of 5 mg/kg the number of horizontal movies, vertical stands and examined holes decreased (Table 1). These effects are attributed to many known nootropic drugs.
cytisine on locomotor activity of mice (n=10)
No. Investigated substances Dose, mg/kg s.c. Number of horizontal movies Number of vertical stands Number of examined holes
1 Control (isotonic NaCl solution) 0.2 8.6 ± 0.8 3.6 ± 0.3 11.2 ± 0.9
2 Piracetam 400 13.8 ± 0.6* 4.6 ± 0.4 16.4 ± 0.7*
3 N-(3-oxy-4-me- thoxy-6-bromobenzoyl) cytisine 0.1 14.2 ± 1.0* 5 ± 1.1 15.6 ± 1.3
0.5 17 ± 1.5* 6.8 ± 0.5* 17.4 ± 1.7*
1.0 17.6 ± 1.4* 8 ± 0.7* 21 ± 1.9*
5.0 18.8 ± 1.2* 6.2 ± 0.4* 18.4 ± 1.6*
4 N-(3-bromo -4-methoxy-benzoyl) cytisine hydrochloride 0.1 7.4 ± 0.7 3.2 ± 0.3 12.2 ± 0.9
0.5 20.2 ± 1.8* 7.4 ± 0.5* 13.5 ± 1.5
1.0 17.8 ± 1.5* 7.6 ± 0.6* 20.8 ± 2.0*
5.0 13 ± 1.0* 5.8 ± 0.4* 14.6 ± 1.3
Note: * P < 0.05
The study of N-(3-hydroxy-4-methoxy-6-bromobenzo-yl) cytisine and N-(3-bromo-4-methoxybenzoyl) cytisine antihypoxant activity on the model of normobaric hypoxia with hypercapnia showed a distinct protective effect, increasing the survival time in comparison with the control
group of animals (Table 2). N-(3-hydroxy-4-methoxy-6-bro-mobenzoyl) cytisine increased the survival time of experimental mice in comparison with the control group at doses of 0.1 and 0.5 mg/kg by 24.4 and 22.4%, respectively, and exceeded piracetam.
Table 2.- Mice survival time in normobaric hypoxia with hypercapnia (n=10)
No. Investigated substances Dose, mg/kg s.c. Survival time, min. Increase of reserve time,%
1 2 3 4 5
1 0.9% NaCl solution (control) 0.2 24.5 ± 3.3 -
2 Piracetam 400 27.2 ± 2.9 11%
1 2 3 4 5
3 N-(3-oxy-4-methoxy-6-bromo-benzoyl) cytisine 0.1 30.5 ± 2.1 24.4%*
0.5 30 ± 2.3 22.4%*
1.0 27.2 ± 1.9 11%
5.0 29 ± 1.5 19.8%*
4 N-(3-bromo-4-methoxybenzo-yl) cytisine hydrochloride 0.1 27.5 ± 2.3 12.2%
0.5 25.6 ± 2.7 4.4%
1.0 27.5 ± 2.9 12.2%
5.0 26.7 ± 2.5 8.9%
Note: * Р < 0.05
The investigated substances showed marked antagonism to the somnolent effect of sodium ethaminal and alcohol intoxication (Tables 3.4). Being preliminary injected before pentylenetetrazole introduction, they increased the latent
Table 3.- Antagonistic effect of investigated substances to ethaminal sodium somnolentent effect (n=10)
No. Investigated substances Dose, mg/kg Somnolent effect duration Effectiveness, %
min %
1 Ethaminal sodium i.p. (control) 50 92.6 ± 8.8 100% -%
2 Pentylenetetrazole s.c. 10 64.7 ± 6.5 69.8% -30.2%*
3 Caffeine s.c. 10 68.4 ± 5.9 73.8% -26.2%*
4 N-(3-oxy-4-methoxy-6-bromo-benzoyl) cytisine hydrochloride s.c. 0.1 76.5 ± 6.8 82.6% -17.4%
0.5 74.2 ± 5.9 80.1% -19.9%
1.0 63.5 ± 6.1 68.5% -31.5%*
5.0 52.8 ± 5.2 57% -43%*
5 N-(3-bromo -4-methoxybenzo -yl) cytisine hydrochloride s.c. 0.1 55.2 ± 5.6 59.6% -40.4%*
0.5 61.4 ± 6.3 66.3% -33.7%*
1.0 46.3 ± 5.0 50% -50%*
5.0 64.2 ± 5.9 69.3% -30.7%*
Note: * Р < 0.05
Table 4.- Antagonistic effect of investigated substances to alcohol intoxication (n=10)
No. Investigated substances Dose, mg/kg Somnolent effect duration Effectiveness, %
min %
1 Ethanol i.p. (control) 4.8 107.5 ± 8.9 100% -%
2 Pentylenetetrazole s.c. 10 75 ± 7.5 69.7% -30.3%*
3 Caffeine s.c. 10 71.4 ± 6.2 66.4% -33.6%*
4 N-(3-oxy-4-methoxy-6-bromo-benzoyl) cytisine hydrochloride s.c. 0.1 77.5 ± 7.9 72% -28%
0.5 74.6 ± 8.0 69.3% -30.7%*
1.0 62.8 ± 6.5 58.4% -41.6%*
5.0 54.2 ± 4.7 50.4% -49.6%*
5 N-(3-bromo -4-methoxybenzo -yl) cytisine hydrochloride s.c. 0.1 79.2 ± 7.9 73.6% -26.4%*
0.5 74.8 ± 6.1 69.5% -30.5%*
1.0 66.2 ± 6.4 61.5% -38.5%*
5.0 64.5 ± 5.8 60% -40%*
Note: *Р < 0.05
period and duration of convulsions (Table 5). The investigated substances at a dose of 1 mg/kg decreased animal death on this model.
Table 5.- Effects of investigated substances on pentylenetetrazole convulsion parameters and animal survival (n=10)
No. Investigated substances Dose, mg/ Starting of con- Duration of con- Mice survival
kg s.c. vulsions, min vulsions, min died survived
1 Pentylenetetrazole (control) 80 5.2 ± 0.6 15.8 ± 2.1 10 0
2 Pyracetam 400 6.4 ± 0.8 19.4 ± 1.9 9 1
N-(3-oxy-4-methoxy-6-bro-mobenzoyl) cytisine hydrochloride 0.1 6.2 ± 0.7 15.2 ± 1.9 10 0
4 0.5 5 ± 0.6 19.7 ± 1.8 9 1
1.0 6 ± 0.8 18.6 ± 2.0 9 1
5.0 7.6 ± 0.5 23.6 ± 1.5 10 0
0.1 4.8 ± 0.4 18.8 ± 1.9 10 0
5 N-(3-bromo-4-methoxyben- 0.5 7 ± 0.6 16.6 ± 2.2 10 0
zoyl) cytisine hydrochloride 1.0 7.8 ± 0.5 20.5 ± 1.5 9 1
5.0 5.6 ± 0.6 17 ± 1.9 10 0
The acute toxicity of N-(3-hydroxy-4-methoxy-6-bro-mobenzoyl) cytisine and N- (3-bromo-4-methoxybenzoyl) cytisine in s.c. introduction was 1275 (1118 ± 1453) mg/kg and 820 (713 ± 943) mg/kg, respectively.
Conclusion: Thus, it has been established that N-(3-hydroxy-4-methoxy-6-bromobenzoyl) cytisine and N-(3-
bromo-4-methoxybenzoyl) cytisine hydrochloride increase research behavior of animals and show antihypoxant and antitoxic activity. These substances are of great interest in searching for new psychotropic drugs among cytisine derivatives.
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