New insights on the arylpiperazinylalkyl pyridazinone ET1 as potent antinociceptive and anti-inflammatory agent
| Autor: | Federica Raucci, Amalia Di Giannuario, Maria Paola Giovannoni, Giorgina Mangano, Letizia Crocetti, Stefano Pieretti, Francesca Marzoli, Mariantonella Colucci, Nicola Mascolo, Francesco Μaione |
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| Přispěvatelé: | Maione, F., Colucci, M., Raucci, F., Mangano, G., Marzoli, F., Mascolo, N., Crocetti, L., Giovannoni, M. P., Di Giannuario, A., Pieretti, S. |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.drug_class Anti-Inflammatory Agents Imidazoline receptor Pain CHO Cells Pharmacology Monocyte Carrageenan Anti-inflammatory 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cricetulus Cricetinae medicine Animals Humans Rats Wistar Receptor Pain Measurement Inflammation Analgesics Dose-Response Relationship Drug Chemistry Pyridazines 030104 developmental biology Nociception HEK293 Cells Mechanism of action Capsaicin Hyperalgesia medicine.symptom Arylpiperazinylalkyl pyridazinone 030217 neurology & neurosurgery Histamine |
| Zdroj: | European journal of pharmacology. 888 |
| ISSN: | 1879-0712 |
| Popis: | Pyridazine derivatives, such as arylpiperazinylalkyl pyridazinones, display antinociceptive effects to thermal and chemical stimuli. Here, we extended our previous knowledge on the pharmacological profile of 4-amino-6-methyl-2-(3-(4-(4-methylcyclohexa-1,3-dien-1-yl)piperazin-1-yl)propyl)-5-vinylpyridazin-3(2H)-one, here referred as ET1, paving the way for the comprehension of its complete mechanism of action. To this aim, we have evaluated the mouse behavioural responses in several animal models of pain, the effect of ET1 in the murine model of zymosan-induced paw oedema and air-pouch, assessing the cytokines and the cellular phenotype and finally, an in vitro radioligand binding study was performed on a panel of 30 different receptors. In the formalin test, ET1 reduced both neurogenic and inflammatory phase of nociception induced by the aldehyde. Similarly, ET1 strongly reduced paw licking response in the capsaicin test, the abdominal stretching in the writhing test and the carrageenan-induced thermal hyperalgesia. ET1 also evoked a long-lasting reduction of thermal hyperalgesia. Furthermore, ET1 produced a long-lasting anti-inflammatory effect in the zymosan-induced mouse paw oedema and air-pouch through the selective inhibition of inflammatory monocytes recruitment and the modulation of IL-1β, IL-6, TNF-α and MCP-1. Binding experiments confirmed an inhibitory effect on adrenergic α1A, α1B and α2A receptors subtypes and, for the first time, a moderate affinity was observed for the following receptors: histamine H1, imidazoline I2, sigma non-opioid intracellular receptor 1 and σ2. These results prompt ET1 as a potent analgesic and anti-inflammatory agent, and support the possibility that it may be suitable for clinical applications in a wide-range of inflammatory-based diseases. |
| Databáze: | OpenAIRE |
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