Design and Synthesis of Potential Multi-Target Antidepressants: Exploration of 1-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-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT[sub.1A]) and dopamine (D[sub.2]) 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 11 and 4 emerged as the lead candidates because of their promising pharmacological profile based on in vitro studies. Compound 11 displayed a high affinity for the 5-HT[sub.1A] (K [sub.i] = 128.0 nM) and D[sub.2] (K [sub.i] = 51.0 nM) receptors, and the SERT (K [sub.i] = 9.2 nM) and DAT (K [sub.i] = 288.0 nM) transporters, whereas compound 4 exhibited the most desirable binding profile to SERT/NET/DAT among the series: K [sub.i] = 47.0 nM/167.0 nM/43% inhibition at 1 µM. These results suggest that compounds 4 and 11 represent templates for the future development of multi-target antidepressant drugs.