Evaluation of anti-depressant effects of phthalazinone-based triple-acting small molecules against 5-HT2A, 5-HT2C, and the serotonin transporter

Jihye Kim, Eunji Cha, Woo Kyu Park, Hye Yeon Lee, Sang Min Lim, Hak Joong Kim, Ae Nim Pae

Research output: Contribution to journalArticlepeer-review

Abstract

Development of highly effective, safe, and fast-acting anti-depressants is urgently required for the treatment of major depressive disorder. It has been suggested that targeting 5-HT2A and 5-HT2C in addition to inhibition of serotonin reuptake may be beneficial in generating anti-depressant agents with better pharmacology and less adverse effects. We have developed phthalazinone-based compounds that potently bind to 5-HT2A, 5-HT2C, and the serotonin transporter. The representative compounds 11j and 11l displayed strong binding affinities against these targets, and showed favorable toxicity profiles as determined by hERG binding and CYP inhibition assays. Furthermore, these compounds presented promising anti-depressant effects comparable to fluoxetine and also synergistic effects with fluoxetine in forced swimming test, which implicates these compounds can be developed to help the treatment of major depressive disorder.

Original languageEnglish
Article number126882
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number4
DOIs
Publication statusPublished - 2020 Feb 15

Keywords

  • 5-HT
  • 5-HT
  • Major depressive disorder
  • Selective serotonin reuptake inhibitor
  • Serotonin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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