Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Exert Antinociceptive Activity in the Tail-Flick and Formalin Test in Rodents and Reveal Reduced Gastrotoxicity

Abstract

Despite the availability of the current drug arsenal for pain management, there is still a clinical need to identify new, more effective, and safer analgesics. Based on our earlier study, newly synthesized 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 10b and 13b, seem to be promising as potential analgesics. The current study was designed to investigate whether novel derivatives attenuate nociceptive response in animals subjected to thermal or chemical noxious stimulus, and to compare this effect to reference drugs. The antinociceptive effect of novel compounds was studied using the tail-flick and formalin test. Pretreatment with novel compounds at all studied doses increased the latency time in the tail-flick test and decreased the licking time during the early phase of the formalin test. New derivatives given at the medium and high doses also reduced the late phase of the formalin test. The achieved results indicate that new derivatives dose-dependently attenuate nociceptive response in both models of pain and exert a lack of gastrotoxicity. Both studied compounds act more efficiently than indomethacin, but not morphine. Compound 13b at the high dose exerts the greatest antinociceptive effect. It may be due to the reduction of nociceptor sensitization via prostaglandin E2 and myeloperoxidase levels decrease.

New N-Substituted-1,2,4-triazole Derivatives of Pyrrolo[3,4-d]pyridazinone with Significant Anti-Inflammatory Activity—Design, Synthesis and Complementary In Vitro, Computational and Spectroscopic Studies

“…Moreover, the macro- and microscopic histopathological assessment of gastric mucosa proved that novel compounds caused negligible stomach lesions andno histopathological changes were observed. These results confirmed the safe gastric profile of investigated molecules [ 36 ].…”

Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test

“…The achieved results concur well with our earlier findings that pretreatment with compound 13b , but not 10b , at the doses of 10 and 20 mg/kg decreased the MPO level in the inflammatory phase of the formalin test. 18 Moreover, Cidade et al 44 demonstrated that some other 1,3,4-oxadiazole derivatives decreased the MPO level in the carrageenan-induced paw edema test.…”

“…Prior to the administration of the appropriate substance, rats were food-deprived for 12 h. Doses of tested compounds and indomethacin were selected based on the earlier works. 11 , 18 , 20 , 21 One hour after appropriate substance administration, the carrageenan-induced paw edema test (carrageenan-induced inflammation) was performed. After the test, blood for biochemical assays was taken from the tail vein, centrifugated (15 min at 4000 rpm), and the obtained serum samples were kept at −80°C until further analysis.…”

“… 12 , 17 In our previous in vivo study, the most promising novel pyrrolo[3,4- d ]pyridazinone derivatives – 6-butyl-3,5,7-trimethyl-1-[[4-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]methoxy]pyrrolo[3,4- d ]pyridazin-4-one and 6-butyl-1-[[4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]methyl]-2-thioxo-1,3,4-oxadiazol-5-yl]methoxy]-3,5,7-trimethyl-pyrrolo[3,4- d ]pyridazin-4-one (hereafter referred to as the compounds 10b and 13b , respectively) – exerted dose-dependent antinociceptive activity with reduced gastrotoxicity in noxious stimuli induced models of pain, ie, the tail-flick and formalin test. 18 It is well known that nociception and inflammation are functionally linked at multiple levels. Tissue damage is detected by both nociceptors that enable pain sensation in the affected area and by tissue-resident cells, which induce an inflammatory response.…”

“…Exudate formation, tissue edema, and inflammatory mediators are responsible for inflammatory pain, and nociception replenishes inflammatory sensors in tissue homeostasis monitoring. 7 , 19 Since compounds 10b and 13b counteract inflammatory nociception in the late phase of the formalin test, compound 13b even in a more efficient way than indomethacin, 18 we decide to assess whether these novel compounds also exert anti-inflammatory action.…”