Synthesis, Potency, and in Vivo Evaluation of 2-Piperazin-1-ylquinoline Analogues as Dual Serotonin Reuptake Inhibitors and Serotonin 5-HT1A Receptor Antagonists

On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3−16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the α1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.