Synthesis and biological evaluation of novel 3-(5-substituted-1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with a dual affinity for serotonin 5-HT1A receptor and SERT

Abstract

The serotonin 1A (5-HT_1A) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT_1A receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D₂, 5-HT_2A, 5-HT₆ and 5-HT₇ receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist-antagonist properties of pre- and postsynaptic 5-HT_1A receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (K_i(5-HT1A) = 10.0 nM; K_i(SERT) = 2.8 nM), good microsomal stability and 5-HT_1A receptor agonistic activity.

Keywords: 5-HT(1A) agonists; 5-HT(1A)/SERT dual activity; Antidepressants; D(2) receptor ligands; Multitarget directed ligand; Serotonin reuptake inhibitors.