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本文引用的文献

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Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity.发现代谢型谷氨酸受体亚型 5 的新型别构调节剂，揭示了其在抗焦虑和抗精神病活性的大鼠行为模型中的化学和功能多样性及体内活性。
Mol Pharmacol. 2010 Dec;78(6):1105-23. doi: 10.1124/mol.110.067207. Epub 2010 Oct 5.
2
Mechanism-based approaches to treating fragile X.基于机制的脆性 X 治疗方法。
Pharmacol Ther. 2010 Jul;127(1):78-93. doi: 10.1016/j.pharmthera.2010.02.008. Epub 2010 Mar 18.
3
Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines.在一系列功能化的区域异构体2-和5-（苯乙炔基）嘧啶中发现可在体外和体内调节代谢型谷氨酸受体亚型5（mGlu5）药理学模式的分子开关。
J Med Chem. 2009 Jul 23;52(14):4103-6. doi: 10.1021/jm900654c.
4
Structure-activity relationships comparing N-(6-methylpyridin-yl)-substituted aryl amides to 2-methyl-6-(substituted-arylethynyl)pyridines or 2-methyl-4-(substituted-arylethynyl)thiazoles as novel metabotropic glutamate receptor subtype 5 antagonists.将N-(6-甲基吡啶基)取代的芳基酰胺与2-甲基-6-(取代芳基乙炔基)吡啶或2-甲基-4-(取代芳基乙炔基)噻唑作为新型代谢型谷氨酸受体亚型5拮抗剂进行构效关系比较。
J Med Chem. 2009 Jun 11;52(11):3563-75. doi: 10.1021/jm900172f.
5
N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors.N-{4-氯-2-[(1,3-二氧代-1,3-二氢-2H-异吲哚-2-基)甲基]苯基}-2-羟基苯甲酰胺（CPPHA）作为I组代谢型谷氨酸受体的正变构调节剂，通过一个新位点发挥作用。
Mol Pharmacol. 2008 Mar;73(3):909-18. doi: 10.1124/mol.107.040097. Epub 2007 Dec 4.
6
Design and synthesis of novel heterobiaryl amides as metabotropic glutamate receptor subtype 5 antagonists.新型杂联芳基酰胺作为代谢型谷氨酸受体5亚型拮抗剂的设计与合成
Bioorg Med Chem Lett. 2007 Apr 1;17(7):2074-9. doi: 10.1016/j.bmcl.2006.12.083. Epub 2007 Jan 4.
7
Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses.代谢型谷氨酸受体5新型正变构调节剂与负变构拮抗剂位点的相互作用是增强受体反应所必需的。
Mol Pharmacol. 2007 May;71(5):1389-98. doi: 10.1124/mol.106.032425. Epub 2007 Feb 15.
8
Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.对用1-甲基-4-苯基-1,2,3,6-四氢吡啶处理的小鼠，代谢型谷氨酸受体mGlu4的药理学激活可减少黑质纹状体变性。
J Neurosci. 2006 Jul 5;26(27):7222-9. doi: 10.1523/JNEUROSCI.1595-06.2006.
9
Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes.N-（1,3-二苯基-1H-吡唑-5-基）苯甲酰胺对大鼠皮质星形胶质细胞中代谢型谷氨酸受体5正变构调节的取代基效应
J Med Chem. 2006 Jun 1;49(11):3332-44. doi: 10.1021/jm051252j.
10
The role of group I metabotropic glutamate receptors in schizophrenia.I 型代谢型谷氨酸受体在精神分裂症中的作用。
Amino Acids. 2007 Feb;32(2):173-8. doi: 10.1007/s00726-006-0319-9. Epub 2006 May 15.

设计并合成取代的 N-(1,3-二苯基-1H-吡唑-5-基)苯甲酰胺作为代谢型谷氨酸受体亚型 5 的正别构调节剂。

Design and synthesis of substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides as positive allosteric modulators of the metabotropic glutamate receptor subtype 5.

机构信息

Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive Baltimore, MD 21224, USA.

出版信息

Bioorg Med Chem Lett. 2011 May 1;21(9):2650-4. doi: 10.1016/j.bmcl.2010.12.110. Epub 2010 Dec 28.

DOI:10.1016/j.bmcl.2010.12.110
PMID:21295978
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3081927/
Abstract

Based on SAR in the alkyne class of mGlu5 receptor negative allosteric modulators and a set of amide-based positive allosteric modulators, optimized substitution of the aryl 'b' ring was used to create substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides. Results from an mGlu5 receptor functional assay, using calcium fluorescence, revealed varying efficacies and potencies that provide evidence that subtle changes in compounds within a close structural class can have marked effects on functional activity including switches in modes of efficacy (i.e., negative to positive allosteric modulation).

摘要

基于 mGlu5 受体负变构调节剂的炔烃类中的 SAR 和一组酰胺基正变构调节剂，优化了芳基 'b' 环的取代基，以合成取代的 N-(1,3-二苯基-1H-吡唑-5-基)苯甲酰胺。使用钙荧光的 mGlu5 受体功能测定的结果表明，功效和效力存在差异，这表明在密切结构类别内的化合物的细微变化可能对功能活性产生显著影响，包括功效模式的转变（即，负变构调节到正变构调节）。