Synthesis and evaluation of a series of 3,4,5-trimethoxycinnamic acid derivatives as potential antinarcotic agents.

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 (20 mg/kg/day). Most of 3,4,5-trimethoxycinnamic acid derivatives were found to have high affinity to 5-HT(1A) receptor. The naloxone-induced morphine withdrawal syndrome was attenuated by (+)8-OH-DPAT (0.1 mg/kg/day, i.p.), a 5-HT(1A) receptor agonist. In cortical neuronal cells, (+)8-OH-DPAT (1 μM) produced an elevation of the pERK 1/2 expression, and the elevated pERK levels were inhibited by WAY 100635, a 5-HT(1A) 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-HT(1A) receptor agonist in mice.

• Authors: Jae-Chul Jung, Sohyeon Moon, Dongguk Min, Woo Kyu Park, Mankil Jung, Seikwan Oh
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 81 Issue 3 Pg. 389-98 (Mar 2013) ISSN: 1747-0285 [Electronic] England
• PMID: 23121934 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 John Wiley & Sons A/S.

Chemical References

• Analgesics
• Cinnamates
• Piperazines
• Pyridines
• Receptors, Serotonin
• Serotonin 5-HT1 Receptor Antagonists
• Receptor, Serotonin, 5-HT1A
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• 3,4,5-trimethoxycinnamic acid
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Analgesics (chemical synthesis, chemistry, pharmacology)
• Animals
• Behavior, Animal (drug effects)
• CHO Cells
• Cells, Cultured
• Cinnamates (chemical synthesis, chemistry, pharmacology)
• Cricetinae
• Cricetulus
• Drug Evaluation, Preclinical
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, metabolism)
• Piperazines (chemistry, pharmacology)
• Protein Binding
• Pyridines (chemistry, pharmacology)
• Receptor, Serotonin, 5-HT1A (chemistry, metabolism)
• Receptors, Serotonin (chemistry, metabolism)
• Serotonin 5-HT1 Receptor Antagonists (chemical synthesis, chemistry, pharmacology)
• Signal Transduction (drug effects)