New Serotoninergic Ligands Containing Indolic and Methyl Indolic Nuclei: Synthesis and in Vitro Pharmacological Evaluation

BACKGROUND: Serotonin is an important biogenic amine and is implicated in wide-ranging physiological and physiopathological processes. Pharmacological manipulation of the serotoninergic system in believed to have a great therapeutic potential. OBJECTIVE: In order to identify selective ligands for 5-HT1A, 5-HT2A and 5-HT2C receptors two series of 4-substituted piperazine derivatives, bearing indolic or methyl indolic nuclei, were synthesized. METHOD: All the compounds, synthesized by standard solution methods, were evaluated towards 5-HT1A, 5-HT2A and 5-HT2C receptors. The highest affine and selective compounds have been evaluated also on dopaminergic (D1 and D2) and adrenergic (α1A and α2A) receptors. RESULTS: Several of the newly synthesized molecules showed affinity in the nanomolar range towards 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, α1A and α2A). CONCLUSION: Compounds 7f and 10a showed a nanomolar affinity towards 5-HT1A with an in vitro pharmacologic profile compatible with antipsychotic drugs.