Department of Chemistry of Drugs, Wrocław Medical University, 1 Tamka Str., Wrocław 50-137, Poland.
Eur J Med Chem. 2011 Oct;46(10):4992-9. doi: 10.1016/j.ejmech.2011.08.006. Epub 2011 Aug 9.
A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced 'writhing' and 'hot plate' test in mice and at radioligand binding assay. At 'writhing' test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED(50) values ranging from 0.04 to 11 mg/kg (i.p.) (ED(50) for ASA--39.15 mg/kg). Analgesic effect at the 'hot plate' test was observed for three compounds 4c,e,f at the dose 3-5 times higher then that of morphine (ED(50)-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described.
一系列 N2-{2-[4-芳基(苄基)-1-哌嗪基(哌啶基)]乙基}吡咯并[3,4-d]哒嗪酮 4 和相关衍生物 5 被合成作为潜在的镇痛剂。新化合物的结构通过微观、光谱和 X 射线分析阐明。在苯并醌诱导的“扭体”和“热板”试验以及放射性配体结合试验中研究了化合物的镇痛活性。在“扭体”试验中，所有化合物都表现出比乙酰水杨酸 (ASA) 更强的活性，ED(50) 值范围为 0.04 至 11 mg/kg（ip）（ASA 的 ED(50)--39.15 mg/kg）。在“热板”试验中，三种化合物 4c、e、f 在 3-5 倍于吗啡的剂量下（ED(50)-3.39 mg/kg）观察到镇痛作用。在 4c、e、f 的放射性配体结合试验中，只有化合物 4f 对μ-阿片受体表现出与曲马多相似的亲和力。吡咯并哒嗪酮 4、5 的急性毒性也进行了研究，在 2000 mg/kg（5a 1420 mg/kg）ip 剂量水平下未观察到毒性作用。基于现有的药理学数据，讨论了 S-A 关系。还描述了 4 的优选构象特征，以 4c 为例。
