Nootropic activity of substituted pyridocinnoline-3-ones

Introduction. Hyperproduction of reactive oxygen species (ROS) has been implicated in the pathogenesis of several neurological and neurodegenerative diseases. Therefore, antioxidants are able to have a positive effect on the functioning of the central nervous system, preventing the development of oxidative stress. Pyridine is one of the most important heterocyclic nuclei providing antiepileptic, antidepressant, sedative, antitumor and antimicrobial effects. The pyridine ring is also a structural component of the compounds under study, 2,5-diaryl-8,8-dimethyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]cinnoline-3-ones. Therefore, we were interested to study the effect of these substituted pyridocinnolin-3-ones on the function of the central nervous system through the evaluation of their nootropic activity.

Target. Study of the nootropic activity of 2,5-diaryl-8,8-dimethyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]cinnolin-3-ones.

Material and methods. 2,5-Diaryl-8,8-dimethyl-3,6,7,8-tetrahydro-2H-pyrido[4,3,2-de]cinnoline-3-ones were selected as the objects of the study. These compounds were prepared by reacting 2-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with arylhydrazines. The first stage in the study of nootropic activity was the assessment of exploratory activity in vivo in the «Open Field» model, which allows assessing motor, exploratory activity and stress level. Motor activity is determined by counting the number of intersections of sectors, research - the number of peeks into the holes and lifts on the hind legs, anxiety – the number of fecal boluses and urination. The number of acts of grooming (self-combing) is also recorded.

Results. The structure of the compounds in order to predict biological activity was analyzed in the PASS online program (probability of nootropic activity (p_a) from 61% to 78%). Motor activity in animals during administration of compounds I, III and V exceeds the value of the reference standard (piracetam) by 21–34%. Pronounced stimulation of research behavior is observed under the influence of compounds I and III, with 28% and 54% higher piracetam, respectively, and mexidol in pyridocinnoline I. Activation of indicative reactions exceeding both reference standards (piracetam and mexidol) by an average of 16%, 34% and 68% is characteristic of samples I, III and V. Thus, pyridocinnolines I, III and V, which contain methyl groups, chlorine and fluorine atoms in their structure, have pronounced indicative research activity. The obtained results are confirmed by the prediction data in the PASS program.

Conclusions. The effect of pyridocinnoline-3-ones on exploratory behavior confirms the expediency and prospects of further pharmacological screening, in particular, the study of their effects on cognitive functions.