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English version: AN INFLUENCE OF AN ETHER AND AMIDES OF 2-OKSOINDOLIN 3-GLYOXILIC ACID ON THE EFFECTS OF SMALL DOSES L-3,4- DIOKSIFENALALANINE
Lutsenko R.V., Sydorenko A.H., Bobyryov V.M.
Higher State educational if Ukraine "Ukrainian Medical Dental Academy", Poltava
The aim of the investigation is to detect the influence of an ether and amides of 2-oksoindolin 3-glyoxilic acid on pharmacological effects of small doses with L-3,4- dioxyphenylalanine e. Materials and methods. It was studied effects of 2- oksoindoiin derivatives (12 mg/ kg) during investigations on the mature males of both sex Wistar's lines. It was studied laboratory codes 18 (amides) and E-38 (ether) during an intake 100 mg/ kg dopamine's precursor. It was investigated a development of exophthalmia, piloerection, hypersolevation in animals an also it was measured a rectal temperature. Results. It was indicated that such substances as L-3,4-dioxyphenylalanine can cause a development of an exophthalmia, piloerection, hypersolevation and also it can increase a rectal temperature in all three periods (30 min, 60 min. and 90 min.). It was compared only by observation by an intake only dopamine's precursor. Effects of amides were compared with activity of imipraminum's preparation in the dose of 25 mg/kg, but the action of the ether decreased of reference-preparation. Conclusion. Received results testify, that in the spectrum of psychopharmacological activity there is an ability to reinforce vegetative effects of L-3,4- dioksifenalalanine by an inhibition of monoaminoacid's enzyme.
Key words: 2-oksoindolin-3- glyoxylic acid derivatives, L-3,4- dioxyphenylalanine, monoamineoxiolose.
Introduction
In the modern conditions of urbanization and a large number of stressful situations that accompany each person every day a steady growth of various types of mental disorders is observed. The latter may induce and exacerbate the course of mental illness. Mental disturbance (of the emotional sphere, intelligence, sleep, etc.) is negatively reflected on the quality of person's life, his or her health and ability to perform social functions [1]. The field of application of pharmacological agents for the correction of mental functions is rather wide, along with psychiatry, these medications are used by specialists of different branches of medicine and are included in standards of treatment of many somatic diseases [15]. Despite the fact that in the world every second new medication that appears on the pharmaceutical market is used for the treatment of diseases of the CNS, there remains a
significant need for the development of new psychotropic drugs. At the same time the existing drugs show insufficient efficacy, low selectivity and are characterized by a large number of side effects [10, 13].
Most substances that selectively interact with the receptors of biologically active substances in the CNS are cyclic nitrogen-containing heterosystems which include derivatives of 2-oksoindoline. The basis for the search of psychotropic drugs in this class of compounds is the data that their effects are realized through interaction with neurally mediated systems of the brain [16]. Therefore, new derivatives of 2-oksoindoline-3-glyoxylic acid are a promising class of substances in terms of studying their pharmacological effects and mechanisms, particularly in relation to the CNS. In the previous studies it was found that derivatives of 2-oksoindoline-3-glyoxylic acid show distinct neuropsychotropic activity, namely anxiolytic, antidepressant, actoprotective and stress protective ones [4, 5, 6].
* To cite this English version: Lutsenko R.V., Sydorenko A.H., Bobyryov V.M. An influence of an ether and amides of 2-oksoindolin 3-glyoxilic acid on the effects of small doses l-3,4- dioksifenalalanine / / Problemy ekologii ta medytsyny. - 2013. - Vol 17, Ns 1-2. - P. 77 -80.
npoSAeMH eKQAorii Ta MCJHUHHH
Goal of research is to determine the influence of ether and amide of derivatives of 2-oksoindoline-3-glyoxylic acid on the pharmacological effects of small doses of L-3,4- Dihydroxyphenylalanine.
Materials and methods of research
50 white eugamic male Wistar rats, kept in standard vivarium conditions in cages of 4-5 animals, were used in the experiments. The experiments were carried out in accordance with the requirements of the European convention "On protection of vertebrate animals used for experimental and other scientific purposes" (Strasbourg, 1985), the Law of Ukraine "On protection of animals from cruel treatment" (№ 3446 - IV 21.02.06). The animals were divided into groups of 10 rats in each.
With the purpose of detecting the compounds of the influence on metabolism of monoamines, particularly on the activity of monoamine oxidase (MAO), the tested rats were injected with L-3,4- Dioxyphenylalanine (L-DOPA) (Sigma-Aldrich, the USA) at a dose of 100 mg/kg of body weight (test group I) and 500 mg/kg (test group II) intrap-eritoneally [8]. The derivatives of 2-oksoindoline-3-glyoxylic acid with laboratory cipher 3-38 (ether) and 18 (amide) were used for the research. Compounds for injection were suspended ex tempore in water, using the emulsifier "Twin-80" (1 drop per 25 mg of the tested substance) and the rats were injected at a dose of 12 mg/kg intraperitoneally 1 hour before medicating 100 mg/kg of L -DOPA. As a reference drug the classical antidepressant imipramine («Egis» Pharmaceutical Ltd, Hungary) was used at a dose of 25 mg/kg of body weight.
The basis of the test was the observation of the animals, during which the following parameters were determined: the occurrence of exophthalmos, piloerection, hy-persalivation, and also rectal temperature was measured after 30 minutes, 60 minutes and 90 minutes after injection of dopamine precursor [8].
The occurrence of exophthalmos was evaluated in points: 0 points - no exophthalmos, 1 point - exophthal-mos on one eye, 2 points - on two eyes. The development of piloerection described the percentage of animals in the group that had such symptom. Hypersalivation was determined by measuring the wet spots on the neck and was expressed in points up to 0.5 cm - 1 point, up to 1 cm - 2 points, up to 2 cm - 3 points; there were no points in case of absence of any stains.
The body temperature of the rats was measured by electrotermometer with rectal receptor, which was injected into the rectum at 1.5-1.8 cm.
Statistical processing of the received results was performed by the program Microsoft Statistic 6.0 using analysis of variance ANOVA and x2 [5].
Results of researches and their discussion
While observing the animals which were injected 100 mg/kg of L-DOPA (test group I) in 30 minutes no pro-
nounced exophthalmos, piloerection and hypersalivation was observed but there was distinctive development of hypothermia. It should be noted that similar changes in autonomic parameters were noted after 60 and 90 minutes from the start of the experiment (Fig., Tabl.).
Injecting rats with precursor of dopamine at a dose of 500 mg/kg (test group II) after 30 minutes caused symptoms characteristic for arousal of autonomic nervous system, namely: there was likely to develop exophthalmos, piloerection and hypersalivation as compared to the testing pathology I. Whereupon marked hyperthermia was observed (see Tab. and Fig.). After 60 minutes from the start of the experiment further increase of occurrence of exophthalmos was marked, piloerection occurred in all cases on the background of further increase of hypersali-vation and hypothermic response. On the last stage of research excessive activation of autonomic nervous system tone was kept caused by an excess of dopamine (Fig., Tabl.).
To study the influence of derivatives of 2-oksoindoline-3-glyoxylic acid on the activity of MAO experiments were carried out with the injection of 100 mg/kg of L-DOPA on their background.
While analyzing the parameters of autonomic balance of animals it was found that the substance 18 in 30 minutes after injection of 100 mg/kg of dopamine precursor potentiated its vegetotropic effects. The value of exoph-thalmos increased in 5.5 times and hypersalivation in 3.5 times versus testing pathology I. Thus piloerection occurred in 40% of rats and probably body temperature increased as compared to the injection of only L-DOPA (see Tab. and Fig.).
In 60 minutes simple amide of 2-oksoindoline continued to potentiate the effects of small doses of cate-cholamine precursor also during subsequent periods of observation. Whereupon on the 90th minute rectal temperature probably did not differ from values of testing pathology II (see Fig.).
Application of the substance with laboratory cipher 338 has probably caused significant potentiation of the effects of small doses of L-DOPA. After 30 minutes from the start of the experiment there was marked exophthal-mos and piloerection that by their expressive were associated with value of the indicators in the group with testing pathology II. Also ether of 2-oksoindoline caused a marked hypersalivation and hyperthermia compared with the injection of the precursor of dopamine (Fig., Tabl.).
In 60 and 90 minutes after injection of 100 mg / kg o L-DOPA the compound 3-38 probably potentiated the development of exophthalmos, piloerection and hyper-salivation as compared to the testing pathology I. Within these terms under the effect of ether 2-oksoindoline a probable increase of rectal temperature was observed as compared to the injection of a small dose of L-DOPA (Fig., Tabl.).
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12345 12345 12345
30 minutes 60 minutes 90 minutes
Figure. The influence of derivatives of 2-oksoindoline-3-glyoxylic acid on the hypothermia caused by injection of small doses (100
mg/kg) of L-3,4-Dihydroxyphenylalanine (n=10).
Notes: 1 - L-3,4-Dihydroxyphenylalanine 100mg/kg (testing pathology I);
2 - L-3,4-Dihydroxyphenylalanine 500mg/kg (testing pathology II);
3 - Imipramine, 25 mg/kg+ L-3,4-Dihydroxyphenylalanine 100 mg/kg;
4 - Compound 18, 12 mg/kg + L-3,4-Dihydroxyphenylalanine 100 mg/kg;
5 -Compound 3-38, 12 mg/kg + L-3,4-Dihydroxyphenylalanine 100 mg/kg;
6 - * - possible differences as compared to testing pathology I;
7 - **- possible differences as compared to testing pathology II.
Application of reference drug imipramine has also po- DOPA was similar to compound 18 but less expressed tentiated the effects of L-DOPA in all periods of observa- than in the compound 3-38 (Fig., Tabl.). tion. Whereupon its ability to potentiate the effects of L-
Table
The influence of derivatives of 2-oksoindoline-3-glyoxylic acid on the effects of small doses of L-3,4-Dihydroxyphenylalanine (100
mg/kg) (n=10)
Groups of animals Exophthalmos, points Piloerection, % Hypersalivation, points
30 60 90 30 60 90 30 60 min- 90
minutes minutes minutes minutes minutes minutes minutes utes minutes
1. L-DOPA 100 mg/kg (testing pathology 1) 0,10+0,10 0,2+0,13 0,20+0,13 10 10 10 0,20+0,13 0,2+0,13 0,2+0,13
2. L-DOPA 500 mg/kg (testing pathology II) P 1-2 1,40+0,16 <0,001 1,8+0,13 <0,001 1,70+0,15 <0,001 90 <0,001(x2) 100 <0,001(x2) 90 <0,001(x2) 1,90+0,23 <0,001 2,5+0,22 <0,001 2,7+0,15 <0,001
3. Imipramine, 25 mg/kg + L-DOPA 100 mg/kg 0,5+0,17 0,7+0,15 0,70+0,15 50 40 40 0,70+0,15 0,7+0,15 0,80+0,25
CL CL <0,05 <0,002 <0,05 <0,001 <0,05 <0,001 <0,02(x2) <0,002(X2) <0,01(X2) <0,001(x2) <0,01(x2) <0,001(x2) <0,05 <0,001 <0,05 <0,001 <0,05 <0,001
4. Compound 18, 12 mg/kg + L-DOPA 100 mg/kg 0,90+0,18 1,1+0,18 0,90+0,17 40 40 40 1,40+0,16 1,3+0,15 1,90+0,27
P 1-4 P 2-4 <0,001 <0,1 <0,001 <0,01 <0,01 <0,01 <0,05(X2) <0,05(X2) <0,01(X2) <0,001(x2) <0,05(x2) <0,001(x2) <0,001 <0,001 <0,001 <0,001 <0,02
5. Compound 3-38, 12 mg/kg + L-DOPA 100 mg/kg 1,60+0,16 1,60+0,16 1,3+0,15 70 80 70 1,36+0,15 1,5+0,34 1,50+0,34
P 1-5 <0,001 <0,001 <0,001 <0,001(x2) <0,001(x2) <0,001(x2) <0,001 <0,01 <0,002
P 2-5 - - <0,1 - - - <0,1 <0,05 <0,01
Therefore, a simple amide and ester 2-oksoindoline potentiated the effects of small doses of dopamine precursor, caused the development of exophthalmos, pilo-erection and hypersalivation and increased rectal temperature. These effects were likely caused by inhibition of MAO, accumulation of dopamine in the central nervous system, leading to arousal of the autonomic nervous system. Inhibiting effect on the enzyme of metabolism of catecholamines was more expressed in the compound 3 -38 and higher than the reference drug effects.
It is described in the literature that biologically active indole derivatives are endogenic MAO inhibitors and have been actively studied [3]. Also among MAO inhibitors there are drugs used as antidepressants, thymoleptic
effect of which may be combined with psychogogic or anxiolytic activity i.e. may have regulatory effects depending on the state of the CNS [12].
It is also recently shown that the inhibition of MAO plays a specific role in the mechanisms of antianxiety effect of atypical ataractics, as described in afobazole [9]. It should be noted that while the inhibition of MAO the excess of do-pamine accumulates in the CNS, which can usually activate presynaptic dopamine receptors of the first type, and thereby presynaptically limit the release of dopamine in the synaptic cleft [13].
The obtained results showed that the derivatives of 2-oksoindoline-3-glyoxylic acid have distinct neurotropic activity in the mechanisms of which inhibition of MAO plays a
npoSAeMH eKQAorii Ta MCJHUHHH
significant role, along with modification of serotonergic transmission [2].
Conclusions:
1. The injection of simple amide and ester among the derivatives of 2-oksoindoline-3-glyoxylic acid at a dose of 12 mg/kg potentiated the effects of small doses of L-of DOPA in rats.
2. Ether 2-oksoindoline, more actively than amide, intensified the effects of the precursor of dopamine, i.e. inhibited MAO.
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Marepian Ha/t'MLUOB qo pe/taKLiii 4.04.2013 p.
