基于哌啶的诺卡因/莫达非尼杂合配体作为高效的单胺转运体抑制剂：通过合理的先导物杂交进行高效药物发现。
Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization.
作者信息
Zhou Jia, He Rong, Johnson Kenneth M, Ye Yanping, Kozikowski Alan P
机构信息
Acenta Discovery, Inc., 9030 S. Rita Road, Suite 300, Tucson, Arizona 85747-9101, USA.
出版信息
J Med Chem. 2004 Nov 18;47(24):5821-4. doi: 10.1021/jm040117o.
Abstract
Some piperidine-based nocaine/modafinil hybrid ligands have been designed, synthesized, and found to display an improved potency at all three monoamine transporters and particularly for DAT and/or NET. Some highly active and selective monoamine transporter inhibitors with low nanomolar to subnanomolar potency were identified. Ligands of this type may find important applications as positron emission tomography imaging tools and in the treatment of central nervous system disorders such as depression and sleep apnea.
摘要
已经设计、合成了一些基于哌啶的诺卡因/莫达非尼杂合配体，发现它们对所有三种单胺转运体都有增强的效力，特别是对多巴胺转运体（DAT）和/或去甲肾上腺素转运体（NET）。鉴定出了一些具有低纳摩尔至亚纳摩尔效力的高活性和选择性单胺转运体抑制剂。这类配体可能作为正电子发射断层扫描成像工具以及在治疗中枢神经系统疾病如抑郁症和睡眠呼吸暂停方面找到重要应用。
相似文献
1
Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization.基于哌啶的诺卡因/莫达非尼杂合配体作为高效的单胺转运体抑制剂：通过合理的先导物杂交进行高效药物发现。
J Med Chem. 2004 Nov 18;47(24):5821-4. doi: 10.1021/jm040117o.
2
Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl)benzylamine with elucidation of bioactive conformation: discovery of 1,4-diazabicyclo[3.3.1]nonane derivatives and evaluation of their biological properties for the monoamine transporters.顺式-(6-二苯甲基哌啶-3-基)苄胺的进一步结构受限类似物及生物活性构象的阐明：1,4-二氮杂双环[3.3.1]壬烷衍生物的发现及其对单胺转运蛋白的生物学性质评估
J Med Chem. 2004 Oct 7;47(21):5101-13. doi: 10.1021/jm049796t.
3
Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors.可卡因哌啶类类似物的进一步构效关系研究。2. 强效多巴胺和5-羟色胺再摄取抑制剂。
J Med Chem. 2000 Mar 23;43(6):1215-22. doi: 10.1021/jm9905561.
4
Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors.某些基于二价配体的单胺再摄取抑制剂作用的药理学和行为学分析
J Med Chem. 2001 May 10;44(10):1615-22. doi: 10.1021/jm000552s.
5
Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors.基于哌啶的单胺转运体抑制剂的进一步构效关系研究：哌啶环立体化学对效力的影响。去甲肾上腺素转运体选择性配体和广谱转运体抑制剂的鉴定。
J Med Chem. 2005 Dec 15;48(25):7970-9. doi: 10.1021/jm050694s.
6
SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement.
J Med Chem. 2002 Jul 18;45(15):3161-70. doi: 10.1021/jm0200153.
7
High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: stereospecific interactions in vitro and in vivo.4-(2-二苯甲氧基乙基)-1-(4-氟苄基)哌啶的高亲和力羟基哌啶类似物与多巴胺转运体的关系：体内外立体特异性相互作用
J Med Chem. 2003 Mar 27;46(7):1220-8. doi: 10.1021/jm020275k.
8
Structure-activity relationship studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: evaluation of O-and N-analogues and their binding to monoamine transporters.4-[2-(二苯基甲氧基)乙基]-1-苄基哌啶衍生物及其N-类似物的构效关系研究：O-和N-类似物的评估及其与单胺转运体的结合
J Med Chem. 2001 Mar 15;44(6):937-48. doi: 10.1021/jm000311k.
9
Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for activity toward monoamine transporters.(3R,4R)-4-(2-(二苯甲氧基)乙基)-1-((R)-2-羟基-2-苯乙基)哌啶-3-醇及其立体异构体对单胺转运体活性的合成与生物学特性研究
ChemMedChem. 2009 Jul;4(7):1075-85. doi: 10.1002/cmdc.200900085.
10
Expansion of structure-activity studies of piperidine analogues of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) compounds by altering substitutions in the N-benzyl moiety and behavioral pharmacology of selected molecules.通过改变N-苄基部分的取代基对1-[2-(二苯基甲氧基)乙基]-4-(3-苯基丙基)哌嗪(GBR 12935)化合物的哌啶类似物进行构效关系研究扩展以及所选分子的行为药理学研究。
J Med Chem. 2002 Jan 31;45(3):654-62. doi: 10.1021/jm010316x.
引用本文的文献
1
Unlocking the Potential of High-Quality Dopamine Transporter Pharmacological Data: Advancing Robust Machine Learning-Based QSAR Modeling.挖掘高质量多巴胺转运体药理学数据的潜力：推进基于稳健机器学习的定量构效关系建模
bioRxiv. 2024 Mar 11:2024.03.06.583803. doi: 10.1101/2024.03.06.583803.
2
Chimeric Structures in Mental Illnesses-"Magic" Molecules Specified for Complex Disorders.精神疾病中的嵌合体结构——指定用于复杂疾病的“神奇”分子。
Int J Mol Sci. 2022 Mar 29;23(7):3739. doi: 10.3390/ijms23073739.
3
Structure Modeling of the Norepinephrine Transporter.去甲肾上腺素转运体的结构建模。
Biomolecules. 2020 Jan 7;10(1):102. doi: 10.3390/biom10010102.
4
Triple reuptake inhibitors as potential next-generation antidepressants: a new hope?三重再摄取抑制剂作为潜在的下一代抗抑郁药：新希望？
Future Med Chem. 2015;7(17):2385-406. doi: 10.4155/fmc.15.134. Epub 2015 Nov 30.
5
Evolutions in fragment-based drug design: the deconstruction-reconstruction approach.基于片段的药物设计进展：解构-重构方法
Drug Discov Today. 2015 Jan;20(1):105-13. doi: 10.1016/j.drudis.2014.09.015. Epub 2014 Sep 27.
6
Simple synthesis of modafinil derivatives and their anti-inflammatory activity.莫达非尼衍生物的简便合成及其抗炎活性。
Molecules. 2012 Sep 3;17(9):10446-58. doi: 10.3390/molecules170910446.
7
Convenient synthesis and biological evaluation of modafinil derivatives: benzhydrylsulfanyl and benzhydrylsulfinyl [1,2,3]triazol-4-yl-methyl esters.方便地合成和生物评价莫达非尼衍生物：苯并[D]硫醚基和苯并[D]亚磺酰基[1,2,3]三唑-4-基甲基酯。
Molecules. 2011 Dec 15;16(12):10409-19. doi: 10.3390/molecules161210409.
8
The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties.新型三重再摄取抑制剂 JZAD-IV-22 具有抗抑郁药理学特性，无运动兴奋剂或敏化特性。
J Pharmacol Exp Ther. 2010 Dec;335(3):762-70. doi: 10.1124/jpet.110.174011. Epub 2010 Sep 23.
9
Norepinephrine transporter inhibitors and their therapeutic potential.去甲肾上腺素转运体抑制剂及其治疗潜力。
Drugs Future. 2004 Dec;29(12):1235-1244. doi: 10.1358/dof.2004.029.12.855246.
本文引用的文献
1
Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine.
J Pharmacol Exp Ther. 2003 Apr;305(1):143-50. doi: 10.1124/jpet.102.046318.
2
Treatment of mood disorders.情绪障碍的治疗。
Nat Neurosci. 2002 Nov;5 Suppl:1068-70. doi: 10.1038/nn943.
3
Monoamine transporter pharmacology and mutant mice.单胺转运体药理学与突变小鼠
Trends Pharmacol Sci. 2002 Aug;23(8):367-73. doi: 10.1016/s0165-6147(02)02044-8.
4
Reinforcing strength of a novel dopamine transporter ligand: pharmacodynamic and pharmacokinetic mechanisms.增强一种新型多巴胺转运体配体的强度：药效学和药代动力学机制。
J Pharmacol Exp Ther. 2002 Oct;303(1):211-7. doi: 10.1124/jpet.102.037812.
5
SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement.
J Med Chem. 2002 Jul 18;45(15):3161-70. doi: 10.1021/jm0200153.
6
Cocaine, reward, movement and monoamine transporters.可卡因、奖赏、运动与单胺转运体
Mol Psychiatry. 2002;7(1):21-6. doi: 10.1038/sj.mp.4000964.
7
The neurobiology of slow synaptic transmission.慢突触传递的神经生物学
Science. 2001 Nov 2;294(5544):1024-30. doi: 10.1126/science.294.5544.1024.
8
Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants.多巴胺能传递增强介导了中枢神经系统兴奋剂的促觉醒作用。
Sleep Res Online. 1998;1(1):49-61.
9
Dopaminergic role in stimulant-induced wakefulness.多巴胺能在兴奋剂诱导的清醒中的作用。
J Neurosci. 2001 Mar 1;21(5):1787-94. doi: 10.1523/JNEUROSCI.21-05-01787.2001.
10
Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors.中枢神经系统中的5-羟色胺、多巴胺和去甲肾上腺素转运体及其抑制剂。
Prog Drug Res. 2000;54:59-119. doi: 10.1007/978-3-0348-8391-7_3.
Zotero 插件