Synthesis and Evaluation of a Series of 3, 4, 5‐Trimethoxycinnamic Acid Derivatives as Potential Antinarcotic Agents. (26th December 2012)

• Record Type: Journal Article
• Authors: Jung, Jae‐Chul; Moon, Sohyeon; Min, Dongguk; Park, Woo Kyu; Jung, Mankil; Oh, Seikwan
• Is Part Of: Chemical biology & drug design. Volume 81:Number 3(2013:Mar.)
• Page Start: 389
• Page End: 398
• Publication Date: 2012-12-26
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12087
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <bold>6–7</bold>, esters <bold>9–12</bold> through condensation reaction, and amides <bold>13–19</bold> 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<sub>1A</sub> receptor. The naloxone‐induced morphine withdrawal syndrome was attenuated by (+)8‐OH‐DPAT (0.1 mg/kg/day, i.p.), a 5‐HT<sub>1A</sub> receptor agonist. In cortical neuronal cells, (+)8‐OH‐DPAT (1 μ<sc>m</sc>) produced an elevation of the pERK 1/2 expression, and the elevated pERK levels were inhibited by WAY 100635, a 5‐HT<sub>1A</sub> 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<sub>1A</sub> receptor agonist in mice.</p> </abstract>