Síntese e avaliação farmacológica de um novo candidato a protótipo de fármaco ansiolítico

Abstract

This paper aimed the design, synthesis and pharmacological evaluation in the central nervous system of a new piperazine derivative (LQFM008) using animal’s behavioral models. The proposed synthetic route to obtain the final compound consisted of three reactions, where the first key intermediate was the phenyl-1H pyrazole (98%) and the second key intermediate was phenyl-1H-pyrazole-4- carbaldeyde (98%) and the final compound, ethyl-4-(( phenyl-1H-pyrazole-4- yl)methyl)piperazine-carboxylate, was obtained in 55% yield. The key intermediates and the final compound were identified by infrared spectroscopy and nuclear magnetic resonance of one and two-dimensional (HSQC and HMBC). Treatment with LQFM008 at doses greater than or equal to 1.1 mmol/kg p.o., s.c or i.p. was neurotoxic, leading to convulsions and death. But the treatment with LQFM008 100, 200 or 400 µmol/kg p.o. did not alter the number of falls in the rota rod, and increased the number of crossings in the center of the open field at 25.46, 24.38 and 28.56%, respectively, and the two highest doses increased the time spent in the center in 47.72 and 45.00%, respectively. All three doses of LQFM008, increased the sleep duration from 107.62±6.30 min (control) to 137.17±10.64, 139.67±10.50 and 171.57±8.32, respectively, without any change in the latency. Treatment with LQFM008 50, 100, 200 and 400 µmol/kg p.o. increased the number of entries in open arm from 36.7±2.86% (control) to 48.5±1.61, 52.8±2.12, 51.1±4.01 and 49.4±4.20%, respectively, as well as increased the time spent in open arm from 31.8±2.33% (control) to 43.3±2.94, 47.8±2.67 and 47.1±5.25%, respectively, and decreased the time spent in central platform from 37.9±2.21% (control) to 29.5±3.01, 28.2±2.90, 26.7±4.70, 26.5±2.01 and 26.4±2.31%, respectively. In the elevated plus maze test, 60 and 90 min after the treatment, LQFM008 200 µmol/kg p.o. increased the number of open arm entries in 63.20 and 60.38%, and the time spent in these arms in 72.39% and 69.31%, respectively, the time spent in central platform was reduced in 28.00% after 15 min, 27.89% after 30 min, 55.32% after 60 min and 45.48% after 90 min. In the light-dark box, 60 and 90 min after the treatment, LQFM008 increased the number of transitions in 95.57% and 141.20%, respectively, and the time spent in the light area in 173.56% after 60 min, and in 216.10% after 90 min. In the elevated plus maze test, treatment with LQFM008 100 µmol/kg p.o. increased the number of entries in the open arms from 25.96±3.01% (control, pre treated with saline i.p. and treated with Tween 2.0% p.o.) to 44.38±3.03%, as well as the time spent in the open arms from 16.60±2.20% (control) to 32.96±2.13% and decreased the time spent in central platform from 51.2±2.56% (control) to 39.1±1.31%. The pre-treatment with a antagonist 5-HT1A NAN-190 1.3 µmol/kg i.p. reverted the effect of LQFM008, decrease the number of entries in open arms to 29.99±3.01%, and the time spent in these arms to 16.78±3.20%, and increase the time spent in central platform in 50.7±2.12%. Animals pre-treated with flumazenil 6.6 µmol/kg i.p. did not differ in any parameters evaluated in relation to controls animals. The anxiolytic-like activity of the compound LQFM008 seems to involve the serotoninergic pathway and but not the GABAA receptor the benzodiazepine sites.