【作者】 张桂森；

【导师】 刘笔锋；

【作者基本信息】 华中科技大学 ， 生物医学工程， 2007， 博士

【摘要】 疼痛已成为影响人们生活质量的一个重要病症。新型非阿片类镇痛药物的研究与开发是目前镇痛药物研究的难点与热点。本论文设计合成了一系列具有镇痛活性的芳烷哌嗪类新化合物,通过其镇痛活性与结构关系研究,优选出候选药物分子,研究了候选药物分子的初步毒性、量效关系、依赖性与动物药代动力学,为寻找具有自主知识产权的镇痛候选新药奠定基础。1、定向设计5个系列芳烷哌嗪衍生物,对设计的化合物进行了合成研究工作,优化了合成线路与工艺。共设计合成6类化合物,合成了62个化合物,其中51个化合物未见文献报道,9个化合物虽有CAS号,但无性状描述。所得化合物结构经核磁共振、质谱确证。2、建立动物镇痛药物筛选模型-热板法与扭体法,用此模型对合成的62个化合物进行镇痛活性的筛选,筛选结果表明有20个化合物有显著的镇痛活性。根据筛选结果,发现并总结了芳烷哌嗪类化合物的结构与镇痛活性的关系:1)苯基哌嗪苯乙酮类化合物具有良好镇痛活性,苯基上有供电子基取代时活性增强,吸电子取代基降低活性;2)苯基被其它杂芳基取代时活性降低;3)苯基与哌嗪之间增加一个碳原子活性保持,但镇静作用增加;苯基上供电子基团取代有利于活性增加,吸电子基团取代活性降低甚至消失;4)羰基肟化时活性显著降低;羰基被亚甲基取代时活性保持,但精神抑制的副作用明显增加。5)哌嗪2、5位被甲基取代时活性降低。3、优选7个镇痛活性优良的化合物进行了急性毒性研究,结果有三个化合物的LD50大于2000 mg/kg,小鼠没有出现明显不良反应,为高度安全的化合物;有三个化合物的LD50大于477 mg/kg,但与其相应的药效学剂量(10、20及40 mg/kg)相比,仍具有较好的安全性。4、优选了6个镇痛活性优良、副作用较小的化合物进行量效关系研究,研究表明:5个化合物的剂量效应曲线为经典的直方双曲线型,一个化合物的剂量效应曲线为倒U型曲线。其中4个化合物的镇痛效价4倍以上于阿斯匹林。5、优选4个化合物采用大鼠纳络酮催促戒断试验进行初步成瘾性研究,初步判断此类化合物无明显成瘾性。6、对优选化合物WG050406-1进行Biege犬初步药代动力学研究,研究表明采用灌胃单次给药250 mg,测得T1/2=0.5-0.9 h,Tmax=1.0 h,Cmax=1000-1200 ng/h,AUC(0-t)=2052 ng h/L,说明此化合物易于吸收,也易于代谢消除。7、建立了芳烷哌嗪类衍生物的化合物库和基于APPRR193药效团叠合的3D-QSAR模型,经验证,该模型不仅能够很好解释实验结果,而且具有较准确的镇痛活性预测能力。更多还原

【Abstract】 Pain is a complex problem with staggering negative health and economic consequences. Non-opioid analgesics are illustrative of the most active fields of research and hopefully represent some of the more promising strategies for discovering more effective and safer pain medications to meet the challenges of the future. For discoverying new analgesic candidates with exclusively intellectual property, in this thesis a series of arylpiperazines with analgesic activity were successfully designed, synthesized and screened on animal models, then the structure-potency relationships were investigated; Furthermore, the toxicity, dose-effect relationship, and addiction as well as pharmacokinetics of the candidates were also studied intensitively.1. Several series of novel arylpiprazines were specifically designed and synthesized. The synthetic processes were fully investigated and optimized technical conditions have also been developed.Sixty-two new compounds were synthesized, and fifty-one of them were reported for the first time and the other nine ones only have CAS number without any detailed description. The structures of these compounds were characterized by NMR and MS.2. The compounds were screened with the in vivo anti-pain agents screening models including hot-plate test and acetic acid-induced abdominal writhing test and found twenty compounds displaying remarkable analgesic activity. The structure-activity relationship (SAR) was demonstrated according to the results obtained: (1) phenyl piperazine acetylbenzene derivative compounds presented dramatic pain-relieving potency,i.e. the potency increased while an electron-donating group was introduced into aromatic ring,In contrast,the potency decreased while an electron-withdrawing group was grafted into aromatic ring. (2) The potency of these compounds declined when phenyl was replaced with other heteroaryl groups; (3) The potency was retained if a carbon atom was added between phenyl and piperazine, but sedative activity was enhanced; (4) The potency significantly lowered if carbonyl was oximated; (5) The potency also reduced if 2, 5 positions of piperazine were substituted by methyl group. 3. Seven compounds displaying remarkable analgesic potency were selected for the acute toxicity evaluation. The LD50 values of three of them exceeded 2000mg/kg, and no side-effects were observed, so they were considered extremely safe. The LD50 determination of the other three ones were more than 477mg/kg and also can be viewed as safe agent compared with its pharmacodynamics dose (10, 20, 40mg/kg).4.Based on the above screening and evaluating system, six compounds with lower side-effect and potent antinociceptive activity were subjected to the next dose-effect relationship study.The results indicated five of them showed a hyperbolic curve, while one exhibited an inverted U-shaped dose response curve.And four compounds have pain-relieving potency four times superior to asipirin.5. Naloxone withdrawal syndromes addictive researchs of the selected compounds were demostrated on mice.The results showed that these compounds possessed no addictive effect.6. The optimized compounds exhibiting the best activity were chosen for pharmacokinetics study on beagles.The data revealed T1/2 is 0.5-0.9 h, Tmax is 1.0 h,Cmax is 1000-1200ng/L,AUC(0-t) is 2052ng h/L through intragastric administration,7. Finally, 3D-QSAR model based on APPRR193 pharmacophore alignment was built to analyze these compounds, the predicted power of model was validated by arylpiperazines focused virtual library and further compound design.更多还原