N-acetyl serotonin derivatives as potent neuroprotectants for retinas

Jianying Shen, Kanika Ghai, Pradoldej Sompol, Xia Liu, Xuebing Cao, P. Michael Iuvone, Keqiang Ye

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

N-acetylserotonin (NAS) is synthesized from serotonin by arylalkylamine N-acetyltransferase (AANAT), which is predominantly expressed in the pineal gland and retina. NAS activates TrkB in a circadian manner and exhibits antidepressant effects in a TrkB-dependent manner. It also enhances neurogenesis in hippocampus in sleep-deprived mice. Here we report the identification of NAS derivatives that possess much more robust neurotrophic effects with improved pharmacokinetic profiles. The compound N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2- oxopiperidine-3-carboxamide (HIOC) selectively activates TrkB receptor with greater potency than NAS. It potently protects retinas from light-induced retinal degeneration (LIRD),which is tightly coupled with pronounced TrkB activation in retinas. Pharmacokinetic studies demonstrate that this compound is stable in serum and liver microsomes. It can pass the blood-brain barrier and blood-retinal barrier. Hence, HIOC is a good lead compound for further drug development for treating retinal degenerative diseases.

Original languageEnglish
Pages (from-to)3540-3545
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number9
DOIs
StatePublished - Feb 28 2012

Keywords

  • Circadian rhythm
  • Melatonin
  • Neurotrophins
  • Small molecule

ASJC Scopus subject areas

  • General

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