Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective alpha(1A)-Adrenoceptor Antagonists
文献类型：期刊论文
| 作者 | Guo, Diliang2; Li, Jing2 ; Lin, Henry4; Zhou, Yu2; Chen, Ying2; Zhao, Fei2; Sun, Haifeng2; Zhang, Dan2; Lin, Honglin1; Shoichet, Brian K.4,5
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2016-10-27 |
| 卷号 | 59期号:20页码:9489-9502 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.6b01217 |
| 文献子类 | Article |
| 英文摘要 | A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as selective alpha(1A)-adrenergic receptors (AR) antagonists for the treatment of benign prostatic hyperplasia. On the basis of the pharmacophore model of the marketed drug silodosin, THPBs were modified by introducing an indole segment into their core scaffolds. In calcium assays, 7 out of 32 compounds displayed excellent antagonistic activities against alpha(1A)-ARs, with IC50 less than 250 nM. Among them, compound (S)-27 had the most potent biological activity; its IC50 toward alpha(1A)-AR was 12.8 +/- 2.2 nM, which is 781 and 20 times more selective than that toward alpha(1B)- and alpha(1D)-AR, respectively. In the functional assay using isolated rat tissues, compound (S)-27 inhibited norepinephrine-induced urethra smooth muscle contraction potently (IC50 = 0.5 +/- 0.3 nM), without inhibiting the aortic contraction (IC50 > 1000 nM), displaying a better tissue selectivity than the marketed drug silodosin. Additional results of preliminary safety studies (acute toxicity and hERG inhibition) and pharmacokinetics studies indicated the potential druggability for compound (S)-27 which is a promising lead for the development of selective alpha(1A)-AR antagonists for the treatment of BPH. |
| WOS关键词 | URINARY-TRACT-SYMPTOMS ; BENIGN PROSTATIC HYPERPLASIA ; ADRENERGIC-RECEPTOR ANTAGONISTS ; AFFINITY RELATIONSHIP INVESTIGATIONS ; ALPHA(1) ADRENOCEPTOR ANTAGONISTS ; OPIOID AGONIST METABOLITES ; ALPHA(1)-ADRENOCEPTOR SUBTYPES ; ANTIPSYCHOTIC SERTINDOLE ; PHENOXY ANALOGS ; SMOOTH-MUSCLE |
| 资助项目 | National Natural Science Foundation of China[21372235] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[21672232] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[81220108025] ; Major Project of Chinese National Programs for Fundamental Research and Development[2015CB910304] ; National S&T Major Projects[2014ZX09507002-001] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000386641300016 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275846]  |
| 专题 | 国家新药筛选中心 药物发现与设计中心 药物化学研究室 |
| 通讯作者 | Xie, Xin; Jiang, Hualiang; Liu, Hong |
| 作者单位 | 1.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Second Mil Med Univ, Sch Pharm, Dept Nat Prod Chem, 325 Guohe Rd, Shanghai 200433, Peoples R China 4.Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA; 5.Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27516 USA; |
| 推荐引用方式 GB/T 7714 | Guo, Diliang,Li, Jing,Lin, Henry,et al. Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective alpha(1A)-Adrenoceptor Antagonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(20):9489-9502. |
| APA | Guo, Diliang.,Li, Jing.,Lin, Henry.,Zhou, Yu.,Chen, Ying.,...&Liu, Hong.(2016).Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective alpha(1A)-Adrenoceptor Antagonists.JOURNAL OF MEDICINAL CHEMISTRY,59(20),9489-9502. |
| MLA | Guo, Diliang,et al."Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective alpha(1A)-Adrenoceptor Antagonists".JOURNAL OF MEDICINAL CHEMISTRY 59.20(2016):9489-9502. |
入库方式： OAI收割
来源：上海药物研究所
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