RESUMO
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.
Assuntos
Analgésicos/síntese química , Cinamatos/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Células Cultivadas , Cinamatos/síntese química , Cinamatos/farmacologia , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Piridinas/química , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The synthesis and biological evaluation of 3,4,5-trimethoxyphenyl acrylamides 1a-f as novel antinarcotic agents are described. The molecules were prepared by the Wittig reaction, followed by a coupling reaction between 3,4,5-trimethoxycinnamic acid (9) and aliphatic amines, which resulted in good yields. When tested for biological activity, compounds 1d-f exhibited strong inhibitory effects on the morphine withdrawal syndrome in mice due to their high binding affinities with serotonergic 5-HT1A receptors.