CN102786483B - 4-(4-苯基哌嗪基)喹唑啉类衍生物的药用用途 - Google Patents

4-(4-苯基哌嗪基)喹唑啉类衍生物的药用用途 Download PDF

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CN102786483B
CN102786483B CN201110130565.8A CN201110130565A CN102786483B CN 102786483 B CN102786483 B CN 102786483B CN 201110130565 A CN201110130565 A CN 201110130565A CN 102786483 B CN102786483 B CN 102786483B
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phenylpiperazinyl
dopamine
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quinazoline derivative
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CN102786483A (zh
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付伟
镇学初
沈庆
熊子君
邓欣贤
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Abstract

本发明属生物制药领域,涉及4-(4-苯基哌嗪基)喹唑啉类衍生物的药用用途,具体涉及4-(4-苯基哌嗪基)喹唑啉类衍生物在制备治疗神经系统疾病药物中的用途,尤其涉及4-(4-苯基哌嗪基)喹唑啉类衍生物在制备多巴胺D3受体抑制剂中的用途。本发明经生物活性测试实验,结果显示,所述的4-(4-苯基哌嗪基)喹唑啉类衍生物对D3受体具有良好的抑制作用,本发明所涉及的化合物可作为药物先导化合物合成多巴胺D3受体抑制剂,进一步用于制备治疗由多巴胺系统功能紊乱引起的精神分裂症及帕金森症药物。

Description

4-(4-苯基哌嗪基)喹唑啉类衍生物的药用用途
技术领域
本发明属生物制药领域,涉及4-(4-苯基哌嗪基)喹唑啉类衍生物的药用用途,具体涉及4-(4-苯基哌嗪基)喹唑啉类衍生物在制备治疗神经系统疾病药物中的用途,尤其涉及4-(4-苯基哌嗪基)喹唑啉类衍生物在制备多巴胺D3受体抑制剂中的用途。
背景技术
精神分裂症(schizophrenia)是临床最常见的一种持续、慢性的重大精神类疾病,其临床表现为阳性症状和阴性症状,前者包括幻觉、妄想、舞蹈症等;后者主要指认知功能缺损、学习记忆障碍、工作记忆障碍等。随着人们工作和生活压力的不断增大,精神问题对整个社会产生严重的不良影响。研究显示,早期的第一代抗精神分裂症药物以治疗阳性症状为主,对阴性症状的疗效甚差,且锥体外系症状(ExtrapyramidalSymptoms,EPS)的发生率高,又称为经典抗精神病药。20世纪60年代末氯氮平问世,该药对精神分裂症阳性症状有很好的疗效,对认知功能障碍也有一定改善,不会发生明显的EPS和运动障碍,称为非经典抗精神病药。在临床使用中发现,抗精神分裂症药氯氮平虽然具有很好的疗效,但部分患者会引起严重的粒细胞减少症,有的甚至发生致死性粒细胞缺乏症。因此,开发结构新颖、低毒副作用的第二代非经典抗精神病药非常必要。
研究表明,精神分裂症的发病原因比较复杂,涉及遗传因素、性格因素、心理因素、环境因素和机体生理因素等,遗传因素在精神分裂症的发病中起重要作用,但其发病机制尚不明确。目前,公认的脑内神经递质不平衡论点指出,(1)病人阳性症状的靶区在皮层下结构,脑内这些区域的多巴胺D2受体功能亢进,产生阳性症状,凡具有D2受体拮抗作用的经典和非经典抗精神病药对阳性症状都有很好疗效;(2)病人的阴性症状和认知功能缺损是由于大脑皮层前额叶上多巴胺D1受体功能低下,而D1受体激动剂能改善学习记忆障碍;(3)D3受体主要位于多巴胺(DA)的边缘通路,与认知和情感功能等有关,而在D2较多的纹状体中几乎不存在D3,因此,对其优先阻滞可产生区域选择性的抗多巴胺能活性,从而产生突出的阳性症状治疗效果;再加上同时还具有突触前D2受体(D2自动受体)拮抗作用,就导致①纹状体的DA含量增加,从而减少EPS;②前额叶皮层的DA含量增加,从而治疗阴性症状及认知功能障碍。另外,D3受体拮抗剂还能降低成瘾,这对于治疗精神分裂症具有重要意义。
计算机辅助药物设计,是一种利用计算化学基本原理,通过模拟药物与受体生物大分子的相互作用或分析已有药物结构与活性的内在关系,合理设计化合物的方法,其高效的先导化合物发现能力已得到广泛认可。
发明内容
本发明的目的是提供4-(4-苯基哌嗪基)喹唑啉类衍生物的药用用途,具体涉及4-(4-苯基哌嗪基)喹唑啉类衍生物在制备治疗神经系统疾病药物中的用途,尤其涉及4-(4-苯基哌嗪基)喹唑啉类衍生物在制备多巴胺D3受体抑制剂中的用途。
本发明所述的神经系统疾病是与多巴胺D3受体相关的神经系统疾病,特别涉及由多巴胺系统功能紊乱引起的精神分裂症及帕金森症;所述的药物具有对多巴胺D3受体的亲和力和作用特性。
本发明的4-(4-苯基哌嗪基)喹唑啉类衍生物可通过下述方法获得:
本发明对最新解析出的多巴胺D3受体晶体结构进行结构优化;对受体配基结合口袋进行活性位点探测;构建受体药效团模型;筛选ASINEX已知化合物数据库(http://www.asinex.com/),从荷兰ASINEX公司购买并测试命中化合物的活性,获得本发明的对D3受体有较高活性的4-(4-苯基哌嗪基)喹唑啉类小分子化合物。
本发明所述的化合物具有式(I)的结构,
(I)
式中
R1:羟乙基哌嗪基,吗啉,哌嗪及N-烷基哌嗪(1-2个碳),二甲氨基,二乙胺基;
R2:氢、卤素、C1-C4烷基、C1-C4取代烷基、羟基、C1-C4烷氧基、C1-C4磺酰基、氰基、含1-4个碳的酰基;
R3:氢、卤素、C1-C4烷基、C1-C4取代烷基、羟基、C1-C4烷氧基、C1-C4磺酰基、氰基、含1-4个碳的酰基;
R4:氢、卤素、C1-C4烷基、C1-C4取代烷基、羟基、C1-C4烷氧基、C1-C4磺酰基、氰基、含1-4个碳的酰基;
所述的式(I)的化合物包括其可用药盐及水合物。
本发明经生物活性测试实验,结果显示,所述的化合物对D3受体具有良好的抑制作用,可用于制备抗精神分裂症及抗帕金森症药物。
本发明所述的式(I)化合物可作为先导化合物,进行结构改造,制备和合成新的多巴胺D3受体抑制剂。
本发明所述的式(I)化合物及其药盐或水合物可用于制备抗精神分裂症及抗帕金森症药物。
为了便于理解,以下将通过具体的附图和实施例对本发明的4-(4-苯基哌嗪基)喹唑啉类衍生物的药用用途进行详细地描述。需要特别指出的是,具体实例和附图仅是为了说明,显然本领域的普通技术人员可以根据本文说明,在本发明的范围内对本发明做出各种各样的修正和改变,这些修正和改变也纳入本发明的范围内。
附图说明
图1是优化后多巴胺D3受体三维结构模型。
图2是基于多巴胺D3受体的药效团模型,其中,包括药效团正电基团、疏水基团、氢键给体基团和氢键受体基团。
具体实施方式
实施例1多巴胺D 3 受体三维结构优化
对最新解析的多巴胺D3受体(EllenY.T.Chien,WeiLiu,QiangZhao,VsevolodKatritch,GyeWonHan,MichaelA.Hanson,LeiShi,AmyHauckNewman,JonathanA.Javitch,VadimCherezov,RaymondC.Stevens.Science330,(2010)1091-1095.PDB号为3PBL)进行能量优化,排除受体中不合理的结构,从而得到了如图1所示优化的D3受体的三维结构。
实施例2多巴胺D 3 受体的活性位点探测及药效团模型的构建。
将多巴胺D3受体结构中保守Asp3.32周围10?范围内的区域定义为GRID程序位点探测的盒子。由于GPCR受体口袋呈负电性,选取四种典型探针:N+(正电探针)、O(氢键受体探针)、N1(氢键给体探针)和DRY(疏水基团探针)分别探测蛋白质中相应的负电、氢键给体、氢键受体和疏水化学环境。依据GRID探针与受体活性口袋的结合能及与氨基酸残基相互作用的性质选取合适的群簇(cluster),计算群簇的几何中心及旋转半径。
使用DiscoveryStudio的Catalyst模块根据以上网格计算和群簇分析结果构建药效团模型。药效基团选择FunctionsOnly,正电、氢键给体、氢键受体和疏水性对应的药效基团分别选POSCHARGE(pos)、HBDONOR(HBD)、HBACCEPTOR(HBA)和HYDROPHOBIC(DRY)。受体关键残基位置定义排除体积(ExcludedVolume,EXT),半径设为1.5?。药效团模型如图2所示。
实施例3基于受体药效团模型的虚拟筛选及生物活性测试
使用DiscoveryStudio程序Catalyst模块的bestflexible方法搜索MayBridge数据库(含有61602个化合物),根据小分子与药效团的匹配值(FitValue)、小分子与受体的对接,G-Score打分函数,及小分子ADMET性质预测结果,由ASINEX小分子数据库(http://www.asinex.com)中挑选7个候选化合物,从荷兰ASINEX公司购买并进行活性测试。
多巴胺D3受体阳性对照品为Spiperone,受试药物和阳性药物均用DMSO溶解至0.01mol/L,然后用去离子水稀释至100μmol/L。将待测化合物与放射性配基各10μL及80μL受体蛋白加入反应试管中,使受试化合物及阳性药物终浓度均为10μmol/L,37℃水浴孵育15min后,即刻移至冰浴终止其反应;在Millipore细胞样品收集器,经过GF/B玻璃纤维滤纸快速抽滤,并用洗脱液(50mMTris-HCl,pH7.7)3mL洗涤3次,用微波炉8~9min烘干,将滤纸移入0.5mL离心管中,加入500μL脂溶性闪烁液。避光静置30min以上,计数测定放射性强度。计算各化合物对同位素配基结合的抑制百分率,抑制率高于90%的化合物进行一系列浓度的受体结合试验,确定半数抑制量(IC50,抑制50%阳性对照药物与受体结合所需化合物浓度)。每浓度测定两副管,每个化合物进行两次独立试验。化合物BAS04932482显示出对D3受体高活性,其抑制率为85.45%,Ki值为806.75±34.58,IC50为1323.1±56.70(如表1所示)。
BAS04932482
表1活性化合物对多巴胺D3受体的抑制率、Ki值和IC50
实验结果显示,化合物BAS04932482对多巴胺D3受体有抑制作用。鉴于多巴胺D3受体与精神分裂症和帕金森症的发病密切相关(JeffreyN.JoyceandMarkJ.Millan.Drugdiscoverytoday10(13):917-925;MinZhang,MichaelEBallard,KathyLKohlhaas,KaitlinEBrowman,Ana-LuciaJongen-Re?lo,LilianeVUnger,GerardBFox,GerhardGross,MichaelWDecker,KarlaUDrescherandLynneERueter.Neuropsychopharmacology(2006)31,1382–1392.),因此,本发明所涉及的化合物可用于制备治疗抗精神分裂症和抗帕金森症的药物。

Claims (4)

1.式I化合物在制备治疗帕金森症药物中的用途;
所述化合物为BAS04932482。
2.按权利要求1所述的用途,其特征在于,所述的药物是多巴胺D3受体抑制剂。
3.按权利要求1所述的用途,其特征在于,所述的化合物包括其可用药盐。
4.按权利要求1或2所述的用途,其特征在于,所述的化合物可用于制备或合成多巴胺D3受体抑制剂。
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