Design and Synthesis of Potential Multi-Target Antidepressants: Exploration of 1-(4-(7-Azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1-indol-3-yl)pyrrolidine-2,5-dione Derivatives with Affinity for the Serotonin Transporter.

We describe the design, synthesis and structure-activity relationship of a novel series of 1-(4-(7-azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT) and dopamine (D) receptors and the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters as multi-target directed ligands for the treatment of depression. All of the tested compounds demonstrated good affinity for the serotonin transporter (SERT). Among them, compounds and emerged as the lead candidates because of their promising pharmacological profile based on in vitro studies. Compound displayed a high affinity for the 5-HT ( = 128.0 nM) and D ( = 51.0 nM) receptors, and the SERT ( = 9.2 nM) and DAT ( = 288.0 nM) transporters, whereas compound exhibited the most desirable binding profile to SERT/NET/DAT among the series: = 47.0 nM/167.0 nM/43% inhibition at 1 µM. These results suggest that compounds and represent templates for the future development of multi-target antidepressant drugs.