Avaliação da atividade antinociceptiva de derivados 3-hidroxi-piperidinil- N-benzil-acilarilidrazônicos em modelos de dor central e neuropática

Abstract

Pain is a worldwide health problem and its treatment is mainly based on drugs, in spite of do not already exist really effective medicines, without adverse effects, for the treatment of the diverse types of pain. Thus, there is a great need for the development of novel potent, effective and secure analgesic drug candidate prototypes, improving pain therapeutics and, most importantly, the individual well-being. In this context, the privileged structure of N-acylhydrazone has been highlighted in the last years with many reported derivatives with antinociceptive activity. Early studies of our research group showed that a series of N-acylhydrazone molecular hybrids, originally developed as multi-target drug prototypes for the treatment of Alzheimer’s disease, exhibited a potential antinociceptive activity. In view of these preliminary results, these compounds were selected as key-structures for an in-depth pharmacological study, searching for a better characterization of the antinociceptive profile and its potential activity in in vivo models of central and neuropathic pain. Therefore, the goal of this work was the synthesis and investigation of the antinociceptive activity of 3-hydroxy-piperidine-N-benzyl-acyl-hydrazone derivatives, as well as their possible mechanism of action. For this purpose, it was used the central pain model of tail flick and the neuropathic pain model of chronic constriction of the sciatic nerve (CCI). The pre-treatment was performed with compounds PQM-56, PQM-65, PQM-67 e PQM-75 at a dose of 100 μmol/Kg (v.o) and morphine (1 mg/Kg) (i.p.), aside treatment with saline or naloxone (30 μg) (i.t.). In the tail flick assay, it was observed a significative increase in the latency time of the animals by the action of PQM-56 in the 1,5 and 3,5 hours and of PQM-75 in the 0,5, 1,5, 3,5 and 6,5 hours, in comparison to the control group. In the neuropathic pain model, the treatment with PQM-56 and PQM-75 also led to a significative increase in the nociceptive threshold in the 0,5, 1,5, 3,5 and 6,5 hours, in comparison to the control group. In both cases, the antinociceptive effect was blocked by treatment with naloxone, indicating that the mechanism of action occurs by via opioid and, therefore, that PQM-56 and PQM-75 have central effect. These results suggest that both substances could represent innovation in the development of new drug candidate prototypes with central antinociceptive action, with potential appliance as neuropathic analgesics, without adverse effects on motor coordination.