Synthesis of new 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives and evaluation for their 5-HT1A and D2 receptor affinity and serotonin transporter inhibition

• Published in: Bioorganic chemistry Vol. 97; p. 103662
• Main Authors: Wróbel, Martyna Z., Chodkowski, Andrzej, Marciniak, Monika, Dawidowski, Maciej, Maksymiuk, Anna, Siwek, Agata, Nowak, Gabriel, Turło, Jadwiga
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2020
• Subjects: 5-HT1A receptor ligands; Depression; Long-chain arylpiperazines; Multi-target ligands; Schizophrenia; LCAPs; SAR; Schizophrenia; Depression; Multi-target ligands; STARD; TLC; Long-chain arylpiperazines; SSRI; 5-HT1A receptor ligands; SERT; ilPFC; 5-HT; DA; PhPs
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103662

[Display omitted] •A series of novel 4-butyl-arylpiperazines-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised.•Compounds were evaluated for their 5-HT1A/D2 receptor affinity and serotonin reuptake inhibition.•All compounds displayed high affinities for 5-HT1A, with Ki values ranging from 0.4 to 44 nM.•4c exhibited mixed receptor profiles for the 5-HT1A/ SERT/D2 receptors (Ki [nM] = 1.3, 64.0 and 182.0, respectively). A series of novel 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesized and evaluated for their 5-HT1A/D2 receptor affinity and serotonin reuptake inhibition. The compounds exhibited high affinity for the 5-HT1A receptor, (especially 4dKi = 0.4 nM) which depended on the substitution pattern at the phenylpiperazine moiety. From this series screen, compound 4c emerged with promising mixed receptor profiles for the 5-HT1A/D2 receptors and the serotonin transporter (Ki = 1.3 nM, 182 nM and 64 nM, respectively).