Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland.
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Int J Mol Sci. 2024 Oct 20;25(20):11276. doi: 10.3390/ijms252011276.
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.
我们描述了一系列新型 1-(4-(7-氮杂吲哚)-3,6-二氢吡啶-1-基)烷基-3-(1-吲哚-3-基)吡咯烷-2,5-二酮衍生物的设计、合成和构效关系，这些化合物对 5-羟色胺 (5-HT) 和多巴胺 (D) 受体具有联合作用，对 5-羟色胺 (5-HT)、去甲肾上腺素 (NA) 和多巴胺 (DA) 转运体具有多靶点定向配体作用，可用于治疗抑郁症。所有测试的化合物均对 5-羟色胺转运体 (SERT) 表现出良好的亲和力。其中，化合物 和 因其在体外研究中的良好药理特性而成为潜在的候选药物。化合物 对 5-HT（=128.0 nM）和 D（=51.0 nM）受体，以及 SERT（=9.2 nM）和 DAT（=288.0 nM）转运体具有高亲和力，而化合物 对 SERT/NET/DAT 具有最理想的结合谱：在 1µM 时对 SERT/NET/DAT 的亲和力分别为 47.0 nM/167.0 nM/43%抑制率。这些结果表明，化合物 和 代表了未来多靶抗抑郁药物开发的模板。
