Novel 4,5-Dihydrothiazole-phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents.

We have described the synthesis of a new series of LCAPs (long-chain arylpiperazine) as serotoninergic ligands (FG 1-18). The combination of structural elements including heterocyclic nucleus, propyl chain and 4,5-dihydrothiazol-2-ylphenylpiperazines, led to the preparation of different derivatives tested for their affinity toward 5-HT1A, 5-HT2A and 5-HT2C receptors. The compounds with better affinity and selectivity binding profiles towards 5-HT1A and 5-HT2C (FG-1, FG-4, FG-5, FG-6, FG-7, FG-8 and FG-18) 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 pharmacological studies showed that compounds FG-1, FG-5, FG-8 and FG-6 exerted antidepressant-like effects and FG-1, FG-18, FG-6 and FG-7 revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compounds seems to be FG-1 which exhibited antidepressant, anxiolytic and anticonvulsant properties, FG-7 and FG-18 which showed features as anxiolytic combine to a pro-cognitive property and notable affinity and selectivity for 5-HT2C receptor, respectively.