5-HT7 receptor modulators: Amino groups attached to biphenyl scaffold determine functional activity

Youngjae Kim, Hyeri Park, Jeongeun Lee, Jinsung Tae, Hak Joong Kim, Sun Joon Min, Hyewhon Rhim, Hyunah Choo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

5-HT7 receptor (5-HT7R) agonists and antagonists have been reported to be used for treatment of neuropathic pain and depression, respectively. In this study, as a novel scaffold for 5-HT7R modulators, we designed and prepared a series of biphenyl-3-yl-methanamine derivatives with various amino groups. Evaluation of functional activities as well as binding affinities of the title compounds identified partial agonists (EC50 = 0.55–3.2 μM) and full antagonists (IC50 = 5.57–23.1 μM) depending on the amino substituents. Molecular docking study suggested that the ligand-based switch in functional activity from agonist to antagonist results from the size of the amino groups and thereby different binding modes to 5-HT7R. In particular, interaction of the ligand with Arg367 of 5-HT7R is shown to differentiate agonists and antagonists. In the pharmacophore model study, two distinct pharmacophore models can tell whether a ligand is an agonist or an antagonist. Taken together, this study provides valuable information for designing novel compounds with selective agonistic or antagonistic properties against 5-HT7R.

Original languageEnglish
Pages (from-to)180-190
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume123
DOIs
Publication statusPublished - 2016 Nov 10

Fingerprint

Scaffolds
Modulators
Ligands
Neuralgia
Inhibitory Concentration 50
Switches
diphenyl
serotonin 7 receptor
Derivatives
Therapeutics

Keywords

  • 5-HT receptor
  • Agonist
  • Antagonist
  • Molecular docking
  • Serotonin

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

5-HT7 receptor modulators : Amino groups attached to biphenyl scaffold determine functional activity. / Kim, Youngjae; Park, Hyeri; Lee, Jeongeun; Tae, Jinsung; Kim, Hak Joong; Min, Sun Joon; Rhim, Hyewhon; Choo, Hyunah.

In: European Journal of Medicinal Chemistry, Vol. 123, 10.11.2016, p. 180-190.

Research output: Contribution to journalArticle

Kim, Youngjae ; Park, Hyeri ; Lee, Jeongeun ; Tae, Jinsung ; Kim, Hak Joong ; Min, Sun Joon ; Rhim, Hyewhon ; Choo, Hyunah. / 5-HT7 receptor modulators : Amino groups attached to biphenyl scaffold determine functional activity. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 123. pp. 180-190.
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