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

doi:10.1016/j.bmcl.2019.126882

Evaluation of anti-depressant effects of phthalazinone-based triple-acting small molecules against 5-HT_2A, 5-HT_2C, and the serotonin transporter

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126882. doi: 10.1016/j.bmcl.2019.126882. Epub 2019 Dec 12.

Authors

Jihye Kim¹, Eunji Cha², Woo Kyu Park³, Hye Yeon Lee², Sang Min Lim⁴, Hak Joong Kim⁵, Ae Nim Pae⁶

Affiliations

¹ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
² Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
³ Bio Platform Technology Research Center, Korea Research Institute of Chemical Technology, Gajeong-ro 141, Yuseong-gu, Daejon 34114, Republic of Korea.
⁴ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address: smlim28@kist.re.kr.
⁵ Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. Electronic address: hakkim@korea.ac.kr.
⁶ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address: anpae@kist.re.kr.

PMID: 31889666
DOI: 10.1016/j.bmcl.2019.126882

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-HT_2A and 5-HT_2C 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-HT_2A, 5-HT_2C, 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.

Keywords: 5-HT(2A); 5-HT(2C); Major depressive disorder; Selective serotonin reuptake inhibitor; Serotonin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / chemistry*
Antidepressive Agents / metabolism
Antidepressive Agents / pharmacology
Azoles / chemistry*
Behavior, Animal / drug effects
Drug Design
Fluoxetine / chemistry
Fluoxetine / pharmacology
Humans
Inhibitory Concentration 50
Mice
Receptor, Serotonin, 5-HT2A / chemistry*
Receptor, Serotonin, 5-HT2A / metabolism
Receptor, Serotonin, 5-HT2C / chemistry*
Receptor, Serotonin, 5-HT2C / metabolism
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / metabolism
Selective Serotonin Reuptake Inhibitors / pharmacology
Serotonin 5-HT2 Receptor Antagonists / chemistry
Serotonin 5-HT2 Receptor Antagonists / metabolism
Serotonin 5-HT2 Receptor Antagonists / pharmacology
Serotonin Plasma Membrane Transport Proteins / chemistry*
Serotonin Plasma Membrane Transport Proteins / metabolism
Structure-Activity Relationship

Substances

Antidepressive Agents
Azoles
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Antagonists
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Fluoxetine