The thesis is devoted to the theoretical generalization and a new solution of the scientific problem associated with improving the efficacy and safety of treatment of depressive and comorbid disorders by studying the innovative active pharmaceutical ingredient 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one (Atristamine) in order to create an effective and safe antidepressant with polymodal effects of the CNS.
The open field test, the elevated plus maze, the tail suspension test, the rotarod-test, the passive-avoidance test after scopolamine-induced amnesia and the model of acute normobaric hypoxic hypoxia with hypercapnia were used for the screening research of ten new 3-(N-R,R′-aminomethyl)-1H-quinolin-4-ones and four derivatives of 4-hydroxy-2 oxoquinoline-3-carboxamides in the doses of 10 and 100 mg/kg. According to the cumulative results of presented and own previous studies, 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one (Atristamine), that showed high antidepressant activity, anti-amnestic effect and psychostimulant properties in the dose of 100 mg/kg, was chosen for in-depth pharmacological study taking into account the set of effects.
The study of secondary pharmacodynamic effects of Atristamine was carried out. Atristamine showed antiamnestic activity, especially in the phases of consolidation of the memory engram (49.7 %) and its reproduction (65.1 %), in the passive avoidance test after scopolamine-induced amnesia in mice. In the Morris water maze, Atristamine (100 mg/kg) markedly enhanced the ability of rats to learn and store spatial memory engrams. It significantly reduced the distance to the platform by 5.1 times and the time to reach the platform by 3.2 times in comparison with intact control. On the model of acute normobaric hypoxic hypoxia with hypercapnia, Atristamine in the dose of 100 mg/kg significantly prolonged the lifespan of animals by 13.6%, but was ineffective on the models of acute hypobaric and acute hemic hypoxia. Atristamine (100 mg/kg) showed actoprotective properties in the weight-loaded swimming test prolonging the swimming time by almost three times (p<0.05) compared to intact control. Cerebroprotective effect of Atristamine (100 mg/kg) was proved on the model of mild traumatic brain injury in rats by reducing the neurological deficit, increasing of activity and emotional reactions (the open field test), improving muscle tone and coordination (the vertical screen test), reducing anxiety (the elevated plus maze), positive effect on cognitive functions (the extrapolation escape task) without deterioration of physical endurance (the weight-loaded swimming test). On this model of trauma, Atristamine most clearly demonstrated antidepressant activity in the Porsolt’s swimming test. Cerebroprotective properties of Atristamine were also confirmed histologically and morphometrically.
The safety studies of Atristamine showed, that after single intragastric introduction LD50 for mice is 6133±568 mg/kg (V toxicity class) and for rats – 4164±309 mg/kg (IV toxicity class). Furthermore, daily intragastric introduction of Atristamine (100 mg/kg) for 28 days in rats of both sexes did not cause significant differences in body weight dynamics, functional parameters of the CNS, heart, urinary and hepatobiliary systems, general blood and urine tests. In addition, it did not affect the mass coefficients of organs and did not change their macroscopic state and histostructure.
According to the cumulative results, Atristamine should be regarded as an antidepressant, which is characterized by polymodal effects on the CNS – additionally exhibits nootropic, antihypoxic, alcoprotective, actoprotective, cerebroprotective and analgesic properties. Low toxicity and safety after repeated administration, rapid development of antidepressant effect, lack of addictive potential and ability to cause physical dependence in spite of proven participation of opioid system in the mechanism of analgesic action, lack of convulsive properties and potentiation of the effects of barbiturates, alcoprotective action and the ability to influence not only the behavioral responses of animals after traumatic brain injury, but also to improve the brain histostructure and to reduce neurological deficit, should be noted among the positive features of Atristamine.
