Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands

A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT_1A and 5-HT_2A serotonergic, α₁ adrenergic, D₁, and D₂ dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT_1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT_1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT _1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT_1A receptor was used to explain the influence of spacer length on ligands affinity.