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Azamatov Azizbek Azamat o'gli, Junior scientist, Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent E-mail: azizbek.azamatov@bk.ru
NOOTROPIC ACTIVITY OF NEW CYTISINE N-BENZOYL DERIVATIVES
Abstract: The new cytisine N-benzoyl derivatives effects on exploratory behavior in the open field, antihypoxic activity on a model of normobaric hypoxia with hypercapnia, anti-narcotic at ethaminal sodium and alcohol intoxication and anticonvulsant activity after pentylenetetrazole injection has been studied in mice. It was established that the investigated substances promote locomotor activity, orienting-exploratory behavior, resistance of brain to hypoxia, and manifested antinarcotic and have a weak anticonvulsant action.
Keywords: Cytisine derivatives, nootropic activity, antihypoxic properties, locomotor activity, convulsions, anesthesia, orienting-exploratory activity.
Introduction and research methods:
More than 2000 derivatives derived from cytisine over the world until now. Institute of the Chemistry of Plant Substances of the Academy of Sciences of the Republic of Uzbekistan has been carrying out targeted synthesis and pharmaco-tox-icological studies among N-benzoyl cytisine derivatives [1].
It was previously found that cytisine derivatives, including N-benzoyl cytisine derivatives, show psychotropic activity [2-8].
In this regard, the purpose of this work was to study the psychotropic activity of new cytisine N-benzoyl derivatives N- (3-benzoyloxy-4-methoxybenzoyl) cytisine hydrochloride and N- (3, 4-dimethoxybenzoyl) cytisine hydrochloride.
The experiments were carried out according to a program involving the use of the most informative and adequate methods for evaluating nootropic substances. The investigated substances were applied subcutaneously to white mice males weighing 18-22 grams. In 30 minutes the effect of the studied compounds on the orienting - exploratory behavior in the open field of 40 x 40 cm pad drawn in 10 x 10 cm squares with 16 rounded holes with diameter of 4 cm was observed for 2 minutes. We registered the number of horizontal displacements by the number of crossed squares, the number of stepping on the hind legs and the number of surveyed holes. Average values of the parameters for the group, standard deviations and confidence intervals were calculated. The investigated substances were administered at doses of 0.1-0.5-1-5 mg/kg. Each dose was tested on 10 mice. A control group of mice under the same experimental conditions were injected with sterile isotonic NaCl solution.
Antihypoxic activity was studied on white male mice of 2122 g using a model ofnormobaric 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 of survival time increasing was calculated relative to the control group. Each dose was tested on 10 animals.
The analeptic effect of investigated substances was evaluated by their antagonism to sodium ethaminal and ethanol. Sodium ethaminal was administered at a dose of 50 mg/kg, alcohol 4.8 g/kg intraperitoneally in 30 minutes after the subcutaneous injection of the studied substances. The duration of anesthesia (lateral position) was recorded.
Anticonvulsant activity was investigated on white mice. 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. Duration of convulsions and time of animal death were recorded.
Acute toxicity assessed on white mice weighing 20-22 grams after subcutaneous injection of the investigated compounds.
Pyracetam - Darnitsa at a dose of 400 mg/kg (Ukraine) was used as a reference drug.
All experimental data on nootropic activity and acute toxicity were calculated using Student's and Litchfield-Wil-coxon methods.
Results and discussion:
Experimental data shown that the studied N-benzoyl derivatives of cytisine showed a high nootropic activity (Table 1).
Table 1. - Effects of cytisine N-benzoyl derivatives on locomotor activity of mice (n = 10)
No. Investigated substance Doses. mg/kg Horizontal movies Vertical stands Holes survey
1 2 3 4 5 6
1. Control group (NaCl solution) 0.2 10.8 ± 1.2 5.3 ± 1.0 12.5 ± 1.2
2. Pyracetam 400 15.8 ± 1.5 8.6 ± 1.2 15.2 ± 1.7
NOOTROPIC ACTIVITY OF NEW CYTISINE N-BENZOYL DERIVATIVES
1 2 3 4 5 6
3. N-(3-benzoyloxy-4-methoxy-benzoyl) cytisine hidrochloride 0.1 18.4 ± 1.6 12.6 ± 1.4 10.2 ± 1.3
0.5 20.2 ± 1.0 13.8 ± 1.2 12.5 ± 1.1
1.0 22.6 ± 1.1 16.2 ± 1.3 21.2 ± 1.5
5.0 15.4 ± 1.2 4.6 ± 0.5 22 ± 1.6
4. N-(3.4-dimethoxybenzoyl) cytisine hydrochloride 0.1 12 ± 1.5 10.4 ± 0.4 8.4 ± 1.4
0.5 12.8 ± 1.2 12.6 ± 1.2 11.6 ± 1.0
1.0 15.2 ± 1.7 15 ± 1.1 14.5 ± 1.1
5.0 11.5 ± 1.5 9.8 ± 1.0 20.8 ± 1.2
As shown in the (Table 1), the test drugs, depending on the administered dose, compared with the control group of animals, increased locomotor and exploring activity of mice for 1.4-1.8 times and exceeded Pyracetam.
Evaluation of antihypoxic activity (Table 2) showed that N-(3,4-methylenedioxybenzoyl) cytisine hydrochloride in-
animals depending on the dose by 25.8-34.8% and exceeded Pyracetam.
The tested substances manifested a noticeable analeptic effect (Tables 3, 4) against sodium ethaminal and ethanhol by shortening the anesthesia duration for 16.2-54.8% and 17.8-51%, accordingly.
creases the reserve time compared to the control group of
Table 2.- Mice survival time in normobaric hypoxia with hypercapnia (n = 10)
No. Investigated substance Doses,mg/kg, s.c. Survival time, min Reserve time increasing,%
1. Control (NaCl solution) 0.2 22,4 ± 0,91 -
2. Pyracetam 400 28,2 ± 0,98 25,8**
3. N-(3-benzoyloxy-4-methoxy-benzoyl) cytisine hidrochloride 0,1 24,8 ± 1,2 10,7**
0.5 26,5 ± 0,85 18,3**
1.0 26.2 ± 0.80 1 . * *
5.0 25.5 ± 0.75 5.6 **
4. N-(3.4-dimethoxybenzoyl) cytisine hydrochloride 0.1 30.2 ± 0.68 34.8*
0.5 28.2 ± 0.82 25.8 **
1.0 30.1 ± 0.9 34.3 *
5.0 29 ± 0.96 29.4 *
Note: * P < 0.01, ** P < 0.05
Table 3.- Investigated substances antagonism to soporific effect of sodium ethaminal (n = 10)
No. Investigated substance Doses. mg/kg, i.p. Sleep duration Effectiveness,%
min %
1. Control (sodium ethaminal) 50 96.2 ± 8.8 100% -%
2. Pyracetam 400 57.4 ± 6.0 59.6% -40.4%*
3. N-(3-benzoyloxy-4-methoxy-benzoyl) cytisine hidrochlo-ride 0.1 58 ± 6.2 60.2% -39.8%**
0.5 60.2 ± 7.8 63.2% -36.8%**
1.0 62.8 ± 8.2 65.2% -34.8%**
5.0 43.5 ± 5.8 45.2% -54.8%*
4. N-(3.4- dimethoxybenzoyl) cytisine hydrochloride 0.1 49.8 ± 7.0 51.7% -48.3%*
0.5 56.4 ± 6.6 58.6% -41.4%*
1.0 78.2 ± 5.8 81.2% -18.8%
5.0 80.7 ± 7.5 83.8% -16.2%
Note: * P < 0.01, ** P < 0.05
Note: * P < 0.01, ** P < 0.05
New cytisine N-benzoyl derivatives showed weak anticonvulsant activity (Table 5).
Table 5.- Anticonvulsant activity of investigated substances (n = 10)
Table 4.- Effect of investigated substances on acute alcohol intoxication (n = 10)
No. Investigated substance Doses, mg/kg, i.p. Sleep d uration Effectiveness,%
min %
1. Control (ethanol 4.8 g/kg) 4.8 94.8 ± 8.2 100% -%
2. Pyracetam 400 69.2 ± 7.0 72.9% -27.1%**
3. N-(3-benzoyloxy-4-methoxybenzoyl) cytisine hidrochloride 0.1 78 ± 7.2 82.2% -17.8%
0.5 72.6 ± 6.4 76.5% -23.5%**
1.0 69.8 ± 7.5 73.6% -26.4%**
5.0 46.5 ± 5.5 49% -51%*
4. N-(3.4-dimethoxybenzoyl) cytisine hydrochloride 0.1 67.2 ± 7.8 70.8% -29.2%**
0.5 64.8 ± 6.3 68.3% -31.7%**
1.0 66.5 ± 6.8 70.1% -29.9%**
5.0 52.4 ± 6.5 55.2% -44.8%*
No. Investigated substance Doses, mg/kg, s.c. Convulsions duration, min Survival
Dead Alive
1. Control (pentylenetetrazole) 80 9.5 10 0
2. Pyracetam 400 23.6 9 1
0.1 16.2 10 0
3. N-(3-benzoyloxy-4-methoxy- 0.5 12.5 9 1
benzoyl) cytisine hidrochloride 1.0 17.6 9 1
5.0 17.4 10 0
0.1 18.4 10 0
4. N-(3.4-dimethoxybenzoyl) 0.5 9.8 8 2
cytisine hydrochloride 1.0 21.5 9 1
5.0 11.4 10 0
The acute toxicity of N- (3-benzoyloxy-4-methoxyben-zoyl) cytisine hydrochloride and N- (3,4-dimethoxybenzoyl) cytisine in subcutaneous administration to white mice was 125(110.6 - 141.l)mg/kg and 131 (115.9 - 148.0)mg/kg, respectively.
Conclusions:
1. New N - benzoyl cytisine derivatives displayed high nootropic activity.
2. Nootropic activity of N- (3-benzoyloxy-4-methoxy-benzoyl) cytisine hydrochloride and N- (3,4-dimethoxyben-zoyl) cytisine hydrochloride exceeds those of nootropic drug Pyracetam.
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