Anxiolytic‐like effects of the new arylpiperazine derivatives containing isonicotinic and picolinic nuclei: behavioral and biochemical studies

Abstract

Anxiety disorder is a great challenge for modern psychopharmacology. Although a variety of single drugs are used in the treatment of anxiety, it is important to search for new therapeutics with faster onset of action, fewer side effects, and higher efficacy. In this work, we studied the possible anxiolytic action mechanism of two new arylpiperazine derivatives: compounds 4p N‐(3‐(4‐(piperonyl)piperazin‐1‐yl)propyl)isonicotinamide and 3o N‐(2‐(4‐(pyrimidin‐2‐yl)piperazin‐1‐yl)ethyl)picolinamide, focusing on their effects on the GABAergic and 5‐HT systems. The elevated plus‐maze test (EPM) was used for measuring anxiety. Additionally, in order to elucidate whether the new compounds have impact on the central redox balance, we conducted biochemical studies. In doing so, the relative activity of the enzymes responsible for glutathione metabolism – glutathione peroxidase and reductase (GPx and GR) – was measured. The results of the presented studies confirmed the anxiolytic effects of the new compounds 4p (60 mg/kg) and 3o (7.5 mg/kg), and suggested in the mechanism of their action, direct 5‐HT1A receptors’ participation and indirect involvement of the GABAergic system. Furthermore, the compounds exerted significant agonistic effect with buspirone (BUS, the 5‐HT1A partial agonist, 1 mg/kg i.p.) and diazepam (DZ, the classic benzodiazepine anxiolytic, 0.25 mg/kg s.c.), while WAY 100635 (N‐{2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl] ethyl}‐N‐(2‐pyridyl) cyclohexanecarboxamide, a selective 5‐HT1A antagonist, 0.1 mg/kg s.c.), but not flumazenil (a GABAA‐BDZ receptor complex antagonist, 10 mg/kg i.p.) was able to reverse their anxiolytic effects in EPM. A concomitant decrease in GPx by the compound 4p (and to a lesser degree, by compound 3o) further seemed to confirm their anxiolytic and antioxidant activity.

Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes

“…in EPM, the animals were pretreated with WAY 100635 (a selective 5-HT 1A receptor antagonist) 0.1 mg/kg subcutaneously (s.c.), or DOI (a 5-HT 2A , 5-HT 2B and 5-HT 2C receptor agonist) 0.25 mg/kg, i.p., 15 min before the compound. Doses and pretreatment times were selected on the basis of literature data and previous experiments in our laboratory 34 . All compounds were administered in a manner generally accepted in experimental pharmacology, in an amount of 10 mL/kg body weight.…”