Giovannoni Maria Paola, Cesari Nicoletta, Vergelli Claudia, Graziano Alessia, Biancalani Claudio, Biagini Pierfrancesco, Ghelardini Carla, Vivoli Elisa, Dal Piaz Vittorio
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.
J Med Chem. 2007 Aug 9;50(16):3945-53. doi: 10.1021/jm070161e. Epub 2007 Jul 13.
A number of 4-amino-5-vinylpyridazinones and 4-amino-5-heterocyclic-pyridazinones were synthesized and tested for their analgesic activity. Many of these compounds, tested at doses of 3-20 mg kg-1 po, showed good antinociceptive activity, reducing by more than 50% the number of writhes with respect to controls. Compounds 16c, 19a, 20a, and 28 were the most potent of the series because they were able to induce a potent antinociceptive effect at a dose of 3 mg kg-1 po. None of the active compounds at the analgesic dose provoked any visible change in normal behavior, as demonstrated in the rotarod test. Studies on the mechanism of action showed that the analgesia induced by the active compounds was completely prevented by pretreatment with the alpha2-antagonist yohimbine, suggesting an involvement of alpha2-adrenoceptors. Further investigation demonstrated an indirect activation of the noradrenergic system through an amplification of noradrenaline release.
合成了多种4-氨基-5-乙烯基哒嗪酮和4-氨基-5-杂环哒嗪酮，并对其镇痛活性进行了测试。其中许多化合物，经口服3-20mg kg-1剂量测试，显示出良好的抗伤害感受活性，与对照组相比，扭体次数减少超过50%。化合物16c、19a、20a和28是该系列中最有效的，因为它们在口服3mg kg-1剂量时能够诱导强烈的抗伤害感受作用。在旋转棒试验中表明，镇痛剂量下的活性化合物均未引起正常行为的任何明显变化。作用机制研究表明，活性化合物诱导的镇痛作用可被α2拮抗剂育亨宾预处理完全阻断，提示α2肾上腺素能受体参与其中。进一步研究表明，通过放大去甲肾上腺素释放间接激活去甲肾上腺素能系统。
