Synthesis and Evaluation of a Series of 3,4,5-Trimethoxycinnamic Acid Derivatives as Potential Antinarcotic Agents

Jae Chul Jung, Sohyeon Moon, Dongguk Min, Woo Kyu Park, Mankil Jung, Seikwan Oh

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

A series of 3,4,5-trimethoxycinnamic acid derivatives was prepared and evaluated for antinarcotic effects on morphine dependence in mice and binding affinities on serotonergic receptors. The key synthetic strategies involve generation of ketones 6-7, esters 9-12 through condensation reaction, and amides 13-19 via coupling reaction using 1-hydroxybenzotriazole/ethyl(dimethylaminopropryl)carbodiimide system in high yield. We found that the naloxone-induced morphine withdrawal syndrome was significantly suppressed by new synthetic 3,4,5-trimethoxycinnamic acid derivatives (20mg/kg/day). Most of 3,4,5-trimethoxycinnamic acid derivatives were found to have high affinity to 5-HT1A receptor. The naloxone-induced morphine withdrawal syndrome was attenuated by (+)8-OH-DPAT (0.1mg/kg/day, i.p.), a 5-HT1A receptor agonist. In cortical neuronal cells, (+)8-OH-DPAT (1μm) produced an elevation of the pERK 1/2 expression, and the elevated pERK levels were inhibited by WAY 100635, a 5-HT1A receptor-specific antagonist. Interestingly, the pERK levels were increased by the 3,4,5-trimethoxycinnamic acid derivatives and the derivatives-mediated changes in pERK levels were blocked by the WAY 100635. These results suggested that new synthetic 3,4,5-trimethoxycinnamic acid derivatives have a potential antinarcotic effect through acting as a 5-HT1A receptor agonist in mice.

Original languageEnglish
Pages (from-to)389-398
Number of pages10
JournalChemical Biology and Drug Design
Volume81
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • 3,4,5-trimethoxycinnamic acids
  • 5-HT1 receptor
  • Binding affinity
  • Coupling reaction
  • Morphine
  • PERK

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