New arylpiperazine derivatives with antidepressant-like activity containing isonicotinic and picolinic nuclei: evidence for serotonergic system involvement

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Synthesis, docking studies, and pharmacological evaluation of 5HT2C ligands containing the N'-cyanoisonicotinamidine or N'-cyanopicolinamidine nucleus

N'-Cyanoisonicotinamidine and N'-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5-HT1A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1 , D2 , α1 , and α2 ). Compound 8e (Ki  = 21.4 nM) was the most affine for the 5-HT2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds 4a and 4c, instead, showed an interesting mixed 5-HT1A /5-HT2C activity with Ki values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5-HT2C (4a, 4c, 8b, and 8e) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that compounds 4a, 8b, and 8e exerted antidepressant-like effects and 4a and 8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be 4a, which displayed antipsychotic-, antidepressant- and anxiolytic-like properties. No side effects, like catalepsy, motor-impairment or ethanol-potentiating effects, were observed after the injection of the tested compounds

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

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

Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study