ABSTRACT
The use of sunscreen has become an indispensable daily routine since UV radiation is a critical environmental stress factors for human skin. This study focused on the design, synthesis, thermal/chemical stability and efficacy/safety evaluations of a new heterocyclic derivative, namely LQFM184, as a photoprotective agent. The compound showed stability when submitted under oxidative and high-temperature conditions. It also revealed an absorption at 260-340 nm (UVA/UVB), with a main band at 298 nm and a shoulder close to 334 nm. LQFM184 showed capacity to interact with other existing UV filters, promoting an increase in the sun protection factor. In relation to acute toxicity, its estimated LD50 was >300-2000 mg kg-1 , probably with a low potential of inducing acute oral systemic toxicity hazard. In addition, our data showed that this compound did not have eye irritation, skin sensitization or phototoxicity potentials. Taken together, these findings make LQFM184 a promising ingredient to be used, alone or in association with other UV filters, in cosmetic products such as sunscreens with a broad spectrum of protection.
Subject(s)
Sunscreening Agents/chemistry , Ultraviolet Rays , 3T3 Cells , Animals , Cattle , Cosmetics/chemistry , Humans , Mice , Mice, Inbred BALB C , Spectrum Analysis/methods , Sunscreening Agents/pharmacology , Sunscreening Agents/toxicity , U937 CellsABSTRACT
BACKGROUND: Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects. AIMS: In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities. METHODS: Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins. RESULTS/OUTCOMES: Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin. CONCLUSIONS/INTERPRETATION: By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.
Subject(s)
Analgesics, Opioid/pharmacology , Antidepressive Agents/pharmacology , Depression/drug therapy , Pain/drug therapy , Analgesics, Opioid/pharmacokinetics , Animals , Antidepressive Agents/pharmacokinetics , Behavior, Animal/drug effects , Disease Models, Animal , Diterpenes, Clerodane , HEK293 Cells , Humans , Locomotion/drug effects , Male , Mice , Models, Molecular , Receptors, Opioid, mu/agonistsABSTRACT
Nonsteroidal anti-inflammatory drugs are commonly used worldwide; however, they have several adverse effects, evidencing the need for the development of new, more effective and safe anti-inflammatory and analgesic drugs. This research aimed to design, synthesize and carry out a pharmacological/toxicological investigation of LQFM-102, which was designed from celecoxib and paracetamol by molecular hybridization. To evaluate the analgesic effect of this compound, we performed formalin-induced pain, hot plate and tail flick tests. The anti-inflammatory effect of LQFM-102 was evaluated in carrageenan-induced paw oedema and pleurisy tests. The biochemical markers indicative of toxicity-AST, ALT, GSH, urea and creatinine-as well as the index of gastric lesion after prolonged administration of LQFM-102 were also analyzed. In addition, the interaction of LQFM-102 with COX enzymes was evaluated by molecular docking. In all experimental protocols, celecoxib or paracetamol was used as a positive control at equimolar doses to LQFM-102. LQFM-102 reduced the pain induced by formalin in both phases of the test. However, this compound did not increase the latency to thermal stimuli in the hot plate and tail flick tests, suggesting an involvement of peripheral mechanisms in this effect. Furthermore, LQFM-102 reduced paw oedema, the number of polymorphonuclear cells, myeloperoxidase activity and TNF-α and IL-1ß levels. Another interesting finding was the absence of alterations in the markers of hepatic and renal toxicity or lesions of gastric mucosa. In molecular docking simulations, LQFM-102 interacted with the key residues for activity and potency of cyclooxygenase enzymes, suggesting an inhibition of the activity of these enzymes.
