Abstract
In this work, we describe a new route for the synthesis and the antinociceptive effects of two new βN-alkanoyl-5-hydroxytryptamides (named C20:0-5HT and C22:0-5HT). The antinociceptive activities were evaluated using well-known models of thermal-induced (reaction to a heated plate, the hot plate model) or chemical-induced (licking response to paw injection of formalin, capsaicin, or glutamate) nociception. The mechanism of action for C20:0-5HT and C22:0-5HT was evaluated using naloxone (opioid receptor antagonist, 1 mg/kg), atropine (muscarinic receptor antagonist, 1 mg/kg), AM251 (cannabinoid CB1 receptor antagonist, 1 mg/kg), or ondansetron (5-HT3 serotoninergic receptor antagonist, 0.5 mg/kg) 30 min prior to C20:0-5HT or C22:0-5HT. The substances both presented significant effects by reducing licking behavior induced by formalin, capsaicin, and glutamate and increasing the latency time in the hot plate model. Opioidergic, muscarinic, cannabinoid, and serotoninergic pathways seem to be involved in the antinociceptive activity since their antagonists reversed the observed effect. Opioid receptors are partially involved due to tolerant mice demonstrating less antinociception when treated with both compounds. Our data showed a quicker and simpler route for the synthesis of the new βN-alkanoyl-5-hydroxytryptamides. Both compounds demonstrated significant antinociceptive effects. These new compounds could be used as a scaffold for the synthesis of analogues with promising antinociceptive effects.
Highlights
As recently revised by the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage [1] causing high health costs and leading to economic loss to society
Compounds I and II were synthesized by mechanochemical amidation reactions, adapted from Strukil et al [30]
The reaction was performed by neat grinding (NG) using three
Summary
As recently revised by the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage [1] causing high health costs and leading to economic loss to society. Severe undesired side effects (i.e., constipation, sedation, tolerance, and dependence) limit clinical opioid use in such a way that their use is widely accepted in cases of severe pain conditions related to cancer or end of life, and its use in chronic opioid therapy remains controversial [2]. Another pharmacological alternative for pain relief is the use of non-steroidal antiinflammatory drugs (NSAIDs). They are important for their analgesic and anti-inflammatory properties and have been widely used for the symptomatic treatment of acute pain, and
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