Резюме
Григорьева Л.В. Поиск новых антипсихотических и психостимулирующих средств среди производных фенилантраниловой кислоты.
Проведено исследование новых 5-сульфамоилзамещенных фенилантраниловой кислоты по тесту взаимодействия с барбитуратами. Наибольший антипсихотический эффект проявило соединение 9, которое в дозе 2,7 мг/кг увеличивает длительность тиопентал-натриевого сна на 180,6%. Замена в фенильном фрагменте молекулы 5-(N,N-диэтилсульфамоил)-N-фенилантраниловой кислоты 3′-метильного (соед. 27) радикала на 2′,5′-диметильный (соед. 29), 2′-метильный (соед. 26), 4′-метильный (соед. 28) приводит к проявлению психостимулирующей активности.
Ключевые слова: 5-сульфамоилзамещенные фенилантраниловой кислоты, антипсихотическая и психостимулирующая активность.
Резюме
Григор’єва Л.В. Пошук нових антипсихотичних і психостимулюючих речовин серед похідних фенілантранілової кислоти.
Проведено дослідження нових 5 - сульфамоілзаміщених фенілантранілової кислоти за тестом взаємодії з барбітуратами. Найбільший антипсихотичний ефект проявила сполука 9 , яка в дозі 2,7 мг / кг збільшує тривалість тіопентал - натрієвого сну на 180,6%. Заміна у фенільному фрагменті молекули 5-(N, N- діетілсульфамоіл)-N- фенілантранілової кислоти 3’- метильного (спол. 27) радикала на 2 ‘ , 5’- діметильний (спол. 29) , 2’- метильний (спол. 26) , 4’- метильний (спол. 28) призводить до прояву психостимулюючої активності.
Ключові слова: 5 - сульфамоілзаміщені фенілантранілової кислоти , антипсихотична і психостимулююча активність.
Summary
Grigorieva L. V. The search for new antipsychotic and psychostimulant use among phenylanthranilic acid derivatives.
The research of new 5-sulfamoilsubstituted phenylanthranilic acid test for interaction with barbiturates. The greatest effect of the antipsychotic compound 9 showed that at a dose of 2,7 mg / kg increases the duration of thiopental sodium sleep 180,6 %. Replacement of the phenyl moiety in the molecule 5 - (N, N-diethylsulfamoyl)-N-phenylanthranilic acid, methyl 3’-(comp. 27) radical 2 ‘, 5’-dimethyl (comp. 29), 2’-methyl (comp. 26), 4’-methyl (comp. 28) leads to the expression of psychostimulant activity.
Key words: 5-sulfamoilsubstituted phenylanthranilic acid, antipsychotic and psychostimulant activity.

Рецензент: д.фарм.н., проф. Б.А. Самура

УДК 615.214.22:547.581.2

Харьковский национальный университет имени В.Н. Каразина

Харьков V. N. Karazin Kharkiv National University

doctor-exclusive@mail.ua

Introduction. In the mid-nineteenth century in clinical practice has been introduced chlorpromazine, whose appearance along with lithium salts was a breakthrough in the world of psychiatry and initiated the era of psychopharmacology. His appearance in the pharmacologists are compared in importance in medicine since the discovery of penicillin. Despite the subsequent development of numerous new drug chlorpromazine and currently continues to be widely used in medical practice [1, 10].

The success of chlorpromazine resulted in a large number of similar products phenothiazine structure [12, 16]. None of them does not exceed chlorpromazine against the main action, but all of these different preparations of additional side effects profiles. In the first decade of the use of neuroleptics identified important features of their actions and to develop optimal indications for their intended purpose. Was identified mechanism of action of these drugs, and the interrelation of the therapeutic effect with a number of side effects caused by a single blocking effect on the dopaminergic system [4, 15].

 Antipsychotic effect of neuroleptics is associated with the blockade of dopamine type 2 (D2) in the structures of the brain. Since the dopaminergic neurons are found in different parts of the brain, along with the main therapeutic effect of antipsychotics have a number of side effects associated with the blockade of dopaminergic transmission in the areas that are responsible for the neurological and neuro-endocrine effects [14]. The blockade of dopamine receptors in the extrapyramidal system leads to the development of undesirable effects such as extrapyramidal disorders (Parkinson's disease, increased muscle tone, salivation), observed in more than 60% of the cases in the treatment of antipsychotic drugs. On the human anti-psychotic drugs have a calming effect, which is accompanied by a decrease in response to external stimuli, the weakening of agitation, the suppression of feelings of fear, a weakening of aggressiveness, and potentiate the effects of sleeping pills, narcotic analgesics, and others [7, 9].

Despite the therapeutic efficacy antipsychotics often produce, including side effects include somnolence, decrease overall background mood, increased seizure activity. In old age, in most cases, developing extrapyramidal disorders: paroxysmal dyskinesia, abnormal heart rhythm, orthostatic collapse, etc. [11, 13].

Attempts to avoid undesirable side effects through application of low doses of drugs leads to treatment resistance, the secondary negative symptoms, which impairs their value [6, 8].

Among the most typical side effects less frequently detected neuroendocrine disorder. These complications of neuroleptic therapy significantly exacerbated by increasing the dosage. The main methods of dealing with the side effects included a selection of safe dose, along with the appointment of corrective therapy. The mechanisms of the side effects are not fully understood. In this regard, a further search for new, more effective and safe drugs was the object of the present work.

Communication with academic programs, plans, themes: the work is done within the framework of the program of research of the National Pharmaceutical University on the topic "Creating new drugs» (№ 01.9.10002381 state registration, code threads BH 10.06.0028.91).

The objective was to study the effect of 5-sulfamoylsubstituted phenylanthranilic acid on the central nervous system of laboratory animals by the test of interaction with the sodium thiopental.

Materials and methods

The object of study was 42 to new substituted phenylanthranilic acid: sodium salts of substituted 5 - (N, N-diethylsulfamoyl)-N-phenyl-anthranilic acid (comp.1-12), potassium salts of substituted 5 - (N, N-diethyl-sulfamoyl) -N-phenylanthranilic acid (comp. 13-24), methyl esters of 5-sulfamoyl-N-phenylanthranilic acid (comp. 25-36) and hydrazide 5 - (N, N-diethylsulfamoyl)-N-phenylanthranilic acid (comp. 37-42), synthesized at the Department of analytical Chemistry, National University of Pharmacy. The structure of the synthesized compounds is confirmed by physico-chemical methods of elemental analysis, UV, IR, NMR and mass spectrometric methods counter synthesis and purity of the synthesized compounds was monitored by TLC.

The study of the interaction of 5-sulfamoilsubstituted phenylanthranilic acid with barbiturates performed on Wistar albino rats weighing 180-200 g of seven animals in each group. Control groups of animals were injected intraperitoneally with thiopental sodium 30 mg / kg, and sleep duration of the group of rats was taken as 100 %. Test compounds were administered at a dose LD50 i.p. 0,02. After 30 minutes, the rats were injected intraperitoneally with thiopental sodium 30 mg / kg. Sleep was evaluated using thiopental duration time during which the rats were in the lateral position since the reflection loss inverting [5]. In the study the animals were kept under standard conditions in accordance with the norms and principles of the EC Council Directive on the protection of vertebrates animals used for research and other scientific purposes [2].

Experimental studies were treated by conventional methods of variation statistics by Student's t test using the software «Windows-2003" and the spreadsheet Excel [3].

Results and discussion

 It is established that most of the sodium salts of substituted 5 - (N, N-diethylsulfamoyl)-N-phenylanthranilic acid (comp. 1-12), showed antipsychotic activity, prolonging the action of sodium thiopental 36,9-180,6 %. The most active compound was 9 - Sodium acid, which is a dose of 2,7 mg / kg increases the duration of thiopental sodium sleep 180,6  % (p <0,01). Replacement of the phenyl moiety 3'-methoxy (comp. 9) radical on 2 ', 4'-dimethyl (comp. 10), 3', 4'-dimethyl (comp. 1) leads to a reduction of antipsychotic activity. Less active potassium salts were substituted 5 - (N, N-diethyl-sulfamoyl)-N-phenylanthranilic acid (comp. 13-24). In this series had the greatest effect of antipsychotic compound 22, which caused an increase in duration of thiopental sodium at 108,1 % (p <0,05). Replacement of the phenyl moiety in the molecule 5 - (N, N-diethylsulfamoyl)-N-phenylanthranilic acid, 2 ', 4'-dimethyl (comp. 18) radical on 4'-methoxy (comp. 17), 3', 5'-dimethyl (comp. 19), 2'-methyl (comp. 14) methyl 4'-(comp. 15) leads to a decrease of antipsychotic activity.

Among methyl esters of 5-sulfamoyl-N-phenylanthranilic acid (comp. 25-36) expressed by prolongation of thiopental sodium sleep caused Compound 36, which in a dose 6,9 mg / kg extended the presence of animals in a lateral position to 131,3 % ( p <0,01). Replacement of the phenyl moiety in the molecule 5 - (N, N-diethylsulfamoyl)-N-phenylanthranilic acid 3'-a methyl (comp. 27) radical 2 ', 5'-dimethyl (comp. 29) and 2'- methyl (comp. 26) methyl 4'-(comp. 28) leads to the appearance of psychostimulant activity, reducing the duration of thiopental sodium.

Substituted hydrazides of 5 - (N, N-diethylsulfamoyl)-N-fenilantranilo-acid (comp. 37-42) showed psychostimulant activity, reducing the duration of thiopental sodium. These substances reduce barbituric sleeping on 11,7-31,2 %. The most pronounced inducing effect was detected in the compound 40, which in a dose of 6.4 mg / kg, caused a decrease in the duration of thiopental sodium sleep 31,2 % (p <0,05). 

Inference

1. The sodium salt acid (comp. 9) revealed antipsychotic activity, increasing duration sodium thiopental sleep 180,6 % (p <0,001).

2. Sulfamoilsubstituted phenylanthranilic acids are a promising group to search for new compounds exhibiting antipsychotic and psychostimulant activity in order to select the most active pharmacological substances for further study.

Table 1

The Impact of Derivatives on the duration of acid phenylanthranilic

Thiopental sodium sleep in rats (n = 7)

Note: * and ** - reliability of results at p <0,05 and p <0,01, respectively, compared with the control.

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