尿道选择性α1-肾上腺素受体拮抗剂药效团的构建

尿道选择性α1-肾上腺素受体拮抗剂药效团的构建

方浩, 卢景芬^*, 夏霖

1.北京大学天然药物与仿生药物国家重点实验室, 北京 100083;
2.中国药科大学药物化学教研室, 南京 210009

收稿日期:2003-04-21 修回日期:2003-11-10 出版日期:2003-12-15 发布日期:2003-12-15
通讯作者: 卢景芬*

Constructing Biophore of Uroselective α1-Adrenoceptor antagonist

FANG Hao, LU Jing-fen^*, XIA Lin

1.State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China;
2.Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China

Received:2003-04-21 Revised:2003-11-10 Online:2003-12-15 Published:2003-12-15
Contact: LU Jing-fen*

摘要/Abstract

摘要： 目的建立具有尿道选择性α1-肾上腺素受体拮抗剂的药效团模型.方法选择对受体亚型和尿道组织均有高亲和力的化合物, 经计算机建模、分子动力学优化、系统搜索得到一系列低能构象, 通过Apex-3D软件计算并构建药效团初步模型, 再参照已有的构效关系数据进行筛选、判别.结果得到3个符合要求的药效团, 它们均含有一个碱性中心和芳环中心, 还存在一个氢位点(HST).结论该模型有助于我们设计、合成活性高且副作用低的新型抗前列腺增生药物.

关键词: α1-肾上腺素受体, 拮抗剂, Apex-3D, 药效团

Abstract: Aim The biophore of uroselective α1-adrenoceptor antagonist was studied by using Apex-3D software on an O2 Silicon Graphics Computer Station. Methods Five known antagonists (Indoramin, GG-818, RS100975, R-YM12167, and KMD-3213), which possess both good selectivity and high affinities to prostate and α1-AR subtype, were chosen for building the biophore. Using an automatic filtering software for obtaining reasonable biophores, the filter parameters were se-lected: P (probability)>0.8, active (number of active compounds)≥4, and size (descriptor center)≥3. Results Three biophores conformed to the requirements, each of whom contained a basic center, an aromatic ring center and H-site according to the structure-activity relationships of known α1-adrenoceptor antagonist. Conclusion The biophore model de-veloped by computer simulation with Apex-3D software can be used to design and synthesize a new α1-adrenoceptor antago-nist with high activity and low side effect.

Key words: α1-adrenoceptor antagonist, α1-adrenoceptor antagonist, uroselectivity, uroselectivity, Apex-3D, Apex-3D, biophore, biophore

中图分类号:

R916.1

916.67

Supporting: ^*Corresponding author. Tel.: 82801517; fax: 82802724

方浩, 卢景芬^*, 夏霖. 尿道选择性α1-肾上腺素受体拮抗剂药效团的构建[J]. .

FANG Hao, LU Jing-fen^*, XIA Lin . Constructing Biophore of Uroselective α1-Adrenoceptor antagonist[J]. .

参考文献

[1] Ziada A, Rosenblum M, Crawford ED. Benign prostatic hyperplasia: an overview [J]. Urology (USA), 1999, 53 (3Suppl 3a): 1-6.
[2] Copper KL, Mckiernan JM, Kaplan SA. α-Adrenoceptor Antagonist in the Treatment of Benign Prostatic Hyperplasia [J]. Drugs, 1999, 57 (1): 9-17.
[3] Hieble JP, Bylund DB, Clarke DE, et al. International union of pharmacology X. Recommendation for alpha-1 adrenoceptors: consensus update [J]. Pharmacol Rev, 1995, 47: 267-270.
[4] Faure C, Pimoule C, Vallancien G, et al. Indentification of α1-adrenoceptor subtypes present in the human proatate [J]. Life Sci, 1994, 54: 1595-1605.
[5] Ford APDW, Arredondo NF, Blue DR, et al. RS-17053, a selectiveα1-adrenoceptor antagonist, displays low affinity for functional α1-adrenoceptor in human protaste: implication for classification [J]. Mol Pharmacol, 1996, 49: 209-215.
[6] Hieble JP, Rufflolo RR, et al. Subclassification and nomenclature ofα1 andα2-adrenoceptor [J]. Prog Drug Res, 1996, 47: 81-129.
[7] Cohen NC, Tschinke V. Generation of new-lead structure in computer-aided drug design [J]. Prog Drug Res, 1995, 45: 205-243.
[8] Golender VE, Vorpagel ER. In: “3D QSAR in drug design: theory, methods and applications” [M]. ESCOM Science Publ: Netherlands, 1993, 133-149.
[9] Apex-3D User Guide, Version 95.0. San Diego: Biosym/MSI Technologies, 1995.
[10] Kenny B, Ballard S, Blagg J, et al. Pharmacological options in the treatment of benign prostatic hyperplasia [J]. J Med Chem, 1997, 40: 1293-1315.
[11] Muramatsu I, Taniguchi T, Okada K. Tamsulosin: α1-adrenoceptor subtype-selectivity and comparison with terazosin [J]. Jpn J Pharmacol, 1998, 78 (3): 331-335.
[12] Williams TJ, Blue DR, Daniels DV, et al. In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α1A-adrenoceptor selective antagonists [J]. Br J Pharmacol,1999, 127(1): 252-258.
[13] Gedge P, Borg F, Connor S, et al. Uroselective α1-adrenoceptor antagonists for the treatment of benign prostatic hypertrophy [J]. Eur J Med Chem, 1995, 30 (Suppl): 300-310.
[14] Testa R, Guarneri L, Ibba M, et al. Antagonism to noradrenaline-induced lethality in rats is related to affinity for the α1A-adrenoceptor subtype[J]. Life Sci, 1997, 61: 2177-2188.

[1]	马宁, 纪超. 乙酰胆碱通过调节IL-1β/IL-1RA平衡改善炎症微环境的机制探讨[J]. 中国药学(英文版), 2023, 32(4): 260-267.
[2]	康静婷, 纪超. 加兰他敏调节IL-1β/IL-1RA比率改善炎症微环境的机制探讨[J]. 中国药学(英文版), 2022, 31(10): 773-781.
[3]	刘园, 陈亚, 胡建星, 刘振明, 张亮仁. 基于药效团模型的人多药耐药相关蛋白内源性底物的预测[J]. 中国药学(英文版), 2017, 26(8): 545-555.
[4]	王俊杰, 王超, 吕鹏, 牛彦, 李宏月, 黄文慧, 李灿, 许凤荣, 梁磊, 徐萍. 异黄酮类CLR/RAMP1拮抗剂的设计、合成及生物活性评价[J]. 中国药学(英文版), 2017, 26(7): 504-511.
[5]	胡琴, 唐惠林, 邵宏. 基于肠促胰素药物治疗2型糖尿病合并非酒精性肝病的疗效和安全性的系统评价和meta分析[J]. 中国药学(英文版), 2016, 25(3): 206-214.
[6]	于博, 金宏威, 张亮仁^, 王超^. 人类尼古丁型乙酰胆碱受体α7亚型激动剂的药效团模型构建及验证[J]. , 2013, 22(5): 393-402.
[7]	齐世光, 于慧, 金宏威, 王占黎^*. TLR7激动剂的三维药效团模型研究[J]. , 2013, 22(2): 148-153.
[8]	杨志瑜, 吕炜, 田然, 金宏威, 曾慧慧^*. 5-羟色胺1A受体配体发现新思路: 基于受体的药效团[J]. , 2009, 18(2): 151-155.
[9]	高广涛, 牛彦, 王栋, 雷小平^, 胡应和^*. 药效团模型法寻找M₁受体激动剂[J]. , 2008, 17(1): 75-78.
[10]	方浩, 卢景芬^*, 夏霖. DDPH衍生物α₁-受体拮抗活性三维定量构效关系的研究[J]. , 2005, 14(3): 149-153.
[11]	管增伟, 王银叶, 杨秀伟, 崔育新. 高圣草素-7-O-β-D-葡萄糖苷抑制血小板活化因子诱导血小板聚集的机理探讨[J]. , 2001, 10(1): 42-44.
[12]	管增伟, 刘雪辉, 刘海新, 崔育新^*. 槲寄生抗血小板激活因子活性成分的研究[J]. , 2000, 9(2): 73-76.
[13]	蒋巡天, 许天林, 华维一, 朱东亚, 余静, 梁少梅. 新型非肽类血管紧张素II受体拮抗剂 2. 喹唑啉酮和喹唑啉衍生物[J]. , 2000, 9(1): 10-14.
[14]	许天林^, 蒋巡天^, 华维一, 倪沛洲, 裴咏梅^. 非肽类纤维蛋白原受体拮抗剂(Ⅱ): N-取代-O-对甲脒苯氧乙基-L-酪氨酸甲酯的合成与抗血小板聚集活性研究[J]. , 1999, 8(4): 201-206.
[15]	蒋巡天, 许天林, 华维一^*, 朱东亚, 余静, 梁少梅. 新型非肽类血管紧张素Ⅱ受体拮抗剂 1.取代的喹啉衍生物 [J]. , 1999, 8(3): 123-134.