多受体药物设计：氟哌啶醇作为设计和合成非典型抗精神病药物的支架。
Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents.
机构信息
Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
出版信息
Bioorg Med Chem. 2012 Feb 1;20(3):1291-7. doi: 10.1016/j.bmc.2011.12.019. Epub 2011 Dec 22.
Abstract
Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that haloperidol can serve as a useful lead in the identification and design of new agents that target multiple receptors associated with antipsychotic pharmacology.
摘要
以氟哌啶醇为骨架，设计了新的化合物来研究与非典型抗精神病药物药理学相关的中枢神经系统受体结合的各种基团的结构贡献。很明显，每个药效团，丁酰苯、哌啶和 4-氯苯基部分，都有助于改变与感兴趣的受体的结合。这一策略已经确定了几种新的化合物，化合物 16、18、19、23、24 和 25，它们的结合谱满足了我们作为潜在非典型抗精神病药物作用的标准。这项研究表明，氟哌啶醇可以作为一种有用的先导化合物，用于识别和设计针对与抗精神病药物药理学相关的多种受体的新型药物。
相似文献
1
Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents.多受体药物设计：氟哌啶醇作为设计和合成非典型抗精神病药物的支架。
Bioorg Med Chem. 2012 Feb 1;20(3):1291-7. doi: 10.1016/j.bmc.2011.12.019. Epub 2011 Dec 22.
2
Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.一种丁酰苯类似物作为潜在非典型抗精神病药物的鉴定：4-[4-(4-氯苯基)-1,4-二氮杂环庚烷-1-基]-1-(4-氟苯基)丁-1-酮。
Bioorg Med Chem. 2008 Aug 1;16(15):7291-301. doi: 10.1016/j.bmc.2008.06.030. Epub 2008 Jun 20.
3
Conformationally constrained butyrophenones with affinity for dopamine (D(1), D(2), D(4)) and serotonin (5-HT(2A), 5-HT(2B), 5-HT(2C)) receptors: synthesis of aminomethylbenzo[b]furanones and their evaluation as antipsychotics.对多巴胺（D(1)、D(2)、D(4)）和5-羟色胺（5-HT(2A)、5-HT(2B)、5-HT(2C)）受体有亲和力的构象受限丁酰苯类化合物：氨甲基苯并[b]呋喃酮的合成及其作为抗精神病药物的评价
J Med Chem. 2000 Nov 30;43(24):4678-93. doi: 10.1021/jm0009890.
4
Synthesis and atypical antipsychotic profile of some 2-(2-piperidinoethyl)benzocycloalkanones as analogues of butyrophenone.一些2-(2-哌啶基乙基)苯并环烷酮作为丁酰苯类似物的合成及非典型抗精神病药概况
J Med Chem. 1994 Aug 5;37(16):2564-73. doi: 10.1021/jm00042a009.
5
Structure-activity relationship studies of SYA 013, a homopiperazine analog of haloperidol.SYA 013 是一种卤吡咯烷的同哌嗪类似物，本研究旨在探讨其构效关系。
Bioorg Med Chem. 2012 Mar 1;20(5):1671-8. doi: 10.1016/j.bmc.2012.01.022. Epub 2012 Jan 21.
6
Synthesis and evaluation of ligands for D2-like receptors: the role of common pharmacophoric groups.D2样受体配体的合成与评价：常见药效基团的作用
Bioorg Med Chem. 2009 Feb 15;17(4):1716-23. doi: 10.1016/j.bmc.2008.12.054. Epub 2008 Dec 31.
7
Conformationally constrained butyrophenones with mixed dopaminergic (D(2)) and serotoninergic (5-HT(2A), 5-HT(2C)) affinities: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo- and -thienocycloalkanones as putative atypical antipsychotics.具有混合多巴胺能（D(2)）和5-羟色胺能（5-HT(2A)、5-HT(2C)）亲和力的构象受限丁酰苯类化合物：作为推定非典型抗精神病药物的（氨基烷基）苯并和噻吩并环烷酮的合成、药理学、三维定量构效关系及分子模拟
J Med Chem. 1999 Jul 29;42(15):2774-97. doi: 10.1021/jm981094e.
8
Current strategies for the development of novel antipsychotic drugs.新型抗精神病药物研发的当前策略。
Mini Rev Med Chem. 2003 May;3(3):239-51. doi: 10.2174/1389557033488169.
9
QF2004B, a potential antipsychotic butyrophenone derivative with similar pharmacological properties to clozapine.QF2004B，一种具有与氯氮平相似药理特性的潜在抗精神病丁酰苯衍生物。
Neuropharmacology. 2006 Aug;51(2):251-62. doi: 10.1016/j.neuropharm.2006.03.021. Epub 2006 May 11.
10
Behavioral pharmacologic studies in the monkey with DD-3480.用DD - 3480对猴子进行的行为药理学研究。
Int J Clin Pharmacol Ther Toxicol. 1982 Jun;20(6):251-4.
引用本文的文献
1
Strategies for Switching between Oral Postsynaptic Antidopaminergic Antipsychotics in Patients with Schizophrenia: A Systematic Review.精神分裂症患者口服突触后抗多巴胺能抗精神病药物之间转换的策略：一项系统综述
CNS Drugs. 2025 Jul 23. doi: 10.1007/s40263-025-01206-3.
2
Ergotamine enhances circadian amplitude and diurnally mitigates nitroglycerin-induced mechanical hypersensitivity.麦角胺可增强昼夜节律幅度，并在白天减轻硝酸甘油诱导的机械性超敏反应。
J Headache Pain. 2025 May 23;26(1):127. doi: 10.1186/s10194-025-02008-0.
3
Dopamine Receptor Ligand Selectivity-An In Silico/In Vitro Insight.多巴胺受体配体选择性——计算机模拟/体外研究洞察
Biomedicines. 2023 May 17;11(5):1468. doi: 10.3390/biomedicines11051468.
4
Differential Role of Active Compounds in Mitophagy and Related Neurodegenerative Diseases.活性化合物在自噬和相关神经退行性疾病中的差异作用。
Toxins (Basel). 2023 Mar 6;15(3):202. doi: 10.3390/toxins15030202.
5
Design, Synthesis and Pharmacological Evaluation of Novel Conformationally Restricted -arylpiperazine Derivatives Characterized as D/D Receptor Ligands, Candidates for the Treatment of Neurodegenerative Diseases.新型构象限制的 -芳基哌嗪衍生物的设计、合成及药理学评价，作为 D/D 受体配体，用于治疗神经退行性疾病的候选药物。
Biomolecules. 2022 Aug 12;12(8):1112. doi: 10.3390/biom12081112.
6
Identification of Novel Dopamine D Receptor Ligands-A Combined In Silico/In Vitro Approach.新型多巴胺 D 受体配体的鉴定——一种计算机辅助/体外结合方法。
Molecules. 2022 Jul 11;27(14):4435. doi: 10.3390/molecules27144435.
7
Computational approaches for the design of novel dopamine D and serotonin 5-HT receptor dual antagonist towards schizophrenia.用于设计新型多巴胺D和5-羟色胺5-HT受体双重拮抗剂治疗精神分裂症的计算方法。
In Silico Pharmacol. 2022 Apr 8;10(1):7. doi: 10.1007/s40203-022-00121-5. eCollection 2022.
8
Sinusoidal analysis reveals a non-linear and dopamine-dependent relationship between ambient illumination and motor activity in larval zebrafish.正弦分析显示，环境光照与幼虫斑马鱼的运动活动之间存在非线性和多巴胺依赖关系。
Neurosci Lett. 2021 Sep 14;761:136121. doi: 10.1016/j.neulet.2021.136121. Epub 2021 Jul 19.
9
New dual 5-HT1A and 5-HT7 receptor ligands derived from SYA16263.新型双重 5-HT1A 和 5-HT7 受体配体源自 SYA16263。
Eur J Med Chem. 2021 Mar 15;214:113243. doi: 10.1016/j.ejmech.2021.113243. Epub 2021 Feb 3.
10
A study of the structure-affinity relationship in SYA16263; is a D receptor interaction essential for inhibition of apormorphine-induced climbing behavior in mice?SYA16263 构效关系研究：D 受体相互作用是否对抑制阿扑吗啡诱导的小鼠攀爬行为至关重要？
Bioorg Med Chem. 2021 Jan 15;30:115943. doi: 10.1016/j.bmc.2020.115943. Epub 2020 Dec 14.
本文引用的文献
1
The 5-HT7 receptor is involved in allocentric spatial memory information processing.5-羟色胺7型受体参与空间记忆信息处理。
Behav Brain Res. 2009 Aug 24;202(1):26-31. doi: 10.1016/j.bbr.2009.03.011. Epub 2009 Mar 19.
2
Synthesis and evaluation of ligands for D2-like receptors: the role of common pharmacophoric groups.D2样受体配体的合成与评价：常见药效基团的作用
Bioorg Med Chem. 2009 Feb 15;17(4):1716-23. doi: 10.1016/j.bmc.2008.12.054. Epub 2008 Dec 31.
3
Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.一种丁酰苯类似物作为潜在非典型抗精神病药物的鉴定：4-[4-(4-氯苯基)-1,4-二氮杂环庚烷-1-基]-1-(4-氟苯基)丁-1-酮。
Bioorg Med Chem. 2008 Aug 1;16(15):7291-301. doi: 10.1016/j.bmc.2008.06.030. Epub 2008 Jun 20.
4
Effect of 5-HT(7) antagonist SB-269970 in the modulation of working and reference memory in the rat.5-羟色胺（7）拮抗剂SB-269970对大鼠工作记忆和参考记忆调节的影响。
Behav Brain Res. 2008 Dec 16;195(1):164-70. doi: 10.1016/j.bbr.2007.12.020. Epub 2008 Jan 9.
5
From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase.封面文章：抗精神病药物诱导的体重增加由组胺H1受体介导的下丘脑AMP激酶激活所致。
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3456-9. doi: 10.1073/pnas.0611417104. Epub 2007 Feb 20.
6
Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid.氟哌啶醇代谢物新功能靶点的鉴定：3-(4-氟苯甲酰基)丙酸非受体依赖性作用的意义。
J Neurochem. 2006 Oct;99(2):458-69. doi: 10.1111/j.1471-4159.2006.04108.x.
7
Time-dependent cognitive deficits associated with first and second generation antipsychotics: cholinergic dysregulation as a potential mechanism.与第一代和第二代抗精神病药物相关的时间依赖性认知缺陷：胆碱能失调作为一种潜在机制。
J Pharmacol Exp Ther. 2007 Mar;320(3):961-8. doi: 10.1124/jpet.106.106047. Epub 2006 Sep 11.
8
The 5-HT2C receptor and antipsychoticinduced weight gain - mechanisms and genetics.5-羟色胺2C受体与抗精神病药物所致体重增加——机制与遗传学
J Psychopharmacol. 2006 Jul;20(4 Suppl):15-8. doi: 10.1177/1359786806066040.
9
The SOHO (Schizophrenia Outpatient Health Outcome) study: implications for the treatment of schizophrenia.SOHO（精神分裂症门诊患者健康结局）研究：对精神分裂症治疗的启示
CNS Drugs. 2006;20(4):293-301. doi: 10.2165/00023210-200620040-00003.
10
Haloperidol: towards further understanding of the structural contributions of its pharmacophoric elements at D2-like receptors.氟哌啶醇：进一步了解其在 D2 样受体上药效基团的结构贡献
Bioorg Med Chem Lett. 2004 Dec 6;14(23):5739-42. doi: 10.1016/j.bmcl.2004.09.046.
Zotero 插件