PSYCHOTROPIC PROPERTIES OF THE POTENTIAL ANTICONVULSANT 1-(4-METOXYPHENYL)-5- {2-[4-(4-METOXYPHENYL) PIPERAZINE-1-YL]-2-OXOETHYL}-1,5-DIHYDRO-4H-PYRAZOLE[3,4-D] PYRYDINE-4-ONE

Abstract

Introduction. In previous studies in experimental models of seizures with different pathogenetic mechanisms was found original derivative pyrazolo [3,4-D] pyridine-4-one - 1- (4-methoxyphenyl) -5- {2 - [4- (4-methoxy-phenyl) piperazine-1-yl] -2-oksoetyl} -1,5-dihydro-4H-pyrazolo[3,4-D] pyridine-4-one - with powerful anticonvulsant activity, polymodal mechanism of action and a wide range of therapeutic doses. However, remain unknown psychotropic properties of this compound, which identify important given the prospects of its implementation in clinical practice.

Investigation methods. The studies were conducted on 85 mature male white mice weighing 18-25 g. Animals were kept in the standard conditions of the National Pharmaceutical University’s Central Scientific and Research Laboratory (temperature 20-25^oC, humidity 50%) in plastic cages on a standard diet with free access to water. Test compound was administered in the most effective anticonvulsant dose of 200 mg / kg intragastric 30 minutes before the experiments. Control mice received purified water by a similar way of 0.1 ml per 10 g body weight. Before the experiments (except interaction with ethanol) animals were kept in a dark cage for 6-8 minutes. Investigation of psychotropic properties was conducted according to the guidelines on the preclinical study in mice.

Results and discussion. The compound significantly reduces motor activity by almost 60%. Reduction of locomotion indicates the predominance of inhibitory processes in the central nervous system. In addition, significantly reduced orienting-research activity at 65%, the amount of total activities - at 62%. There was a trend towards to the reduction of emotion. Together this results indicate sedative properties of the compound. Compound was not significantly affected on the depressive behavior. There was only a tendency to increase the latent period of the first hovering at 40%, total time and number of hangs at 17%, which can be interpreted as a slight antidepressant property. Revealed a significant decrease in the number of visits dark sleeveless in the test of elevated plus-labyrinth that can be considered weak anxiolitic action. The time spent in light areas of labyrinth and latency period of entry to dark sleeves were increased at 20% and 100% respectively. However, it was only trend. In addition, vegetative emotional reactions have been reduced in 5.5 times (p <0.05), which also indicates a decrease in anxiety animals. Mild anxiolytic effect may be related to GABA-positive mechanism of action of compounds that found in previous studies of antagonism to pentylentetrazol and with adrenergic mechanism, which shows distinct antagonism to caffeine (adenosine and GABA are an inhibitory neurotransmitters). Test compound hasn't myorelaxant activity and not violate the coordination of movements. As result anticonvulsant action is selective without violations muscle tone. In the test passive avoidance under scopolamine amnesia latent period of entry to dark chamber and the number of mice that reached the criterion of training statistically significant decreased in 3.5 times and at 69% relatively intact control after 24 hours. This indicate memory impairment by M-anticholinergics. However, administration of test compound caused scopolamine effect abolition by significantly increasing the latent period of entry to dark chamber up to the level of intact control and the number of trained mice. Antiamnesic activity is 110%. In addition, on the beginning of test in the mice administered a test compound latent period of entry to dark chamber was significant higher than that of the intact control (in 4,7 times) and scopolamine control (1,8). Presumably increased latency period associated with the presence of mild sedative and anxiolytic effects revealed by the previous tests. Antagonism to scopolamine can testify in favor cholinergic properties of test compound. The compound does not enhance inhibitory effect of ethanol, which is a favorable feature.

Conclusions.

1. The effect of 1-(4-metoxyphenyl)-5-{2-[4-(4-metoxyphenyl) piperazine-1-yl]-2-oxoethyl}-1,5-dihydro-4H-pyrazole[3,4-D] pyrydine-4-one on behavioral responses, depression and anxiety, muscle tone and coordination, memory of experimental animals and interaction with neurotropic substances inhibitory action have been investigated.

2. 1- (4-Methoxyphenyl) -5- {2- [4- (4-methoxy-phenyl) piperazine-1-yl] -2-oksoetyl} -1,5-dihydro-4H-pyrazolo [ 3,4-D] pyridine-4-one 200 mg / kg has sedative effect, reveals antiamnesic properties and weak anxiolytic effect.

3. The test compound does not affect depressive behavior, has no negative effects on skeletal muscle tone and coordination, does not potentiate the effect of ethanol.