开发一种新型的、可穿透中枢神经系统的代谢型谷氨酸受体 3（mGlu3）别构调节剂（NAM）探针（ML289），该探针源自与之密切相关的 mGlu5 部分激动剂。
Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM.
机构信息
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3921-5. doi: 10.1016/j.bmcl.2012.04.112. Epub 2012 Apr 30.
Abstract
Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC(50) value of 0.66 μM and is inactive against mGlu(5).
摘要
在此，我们报告了一种新型代谢型谷氨酸受体 3（mGlu(3)）别构调节剂（NAM）探针 ML289 的发现和 SAR 研究，其对 mGlu(2)的选择性是 15 倍。mGlu(3)NAM 是通过与强效的 mGlu(5)正变构调节剂（PAM）VU0092273 相关的“分子开关”发现的。这种 NAM（VU0463597，ML289）的 IC(50)值为 0.66 μM，对 mGlu(5)无活性。
相似文献
1
Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM.开发一种新型的、可穿透中枢神经系统的代谢型谷氨酸受体 3（mGlu3）别构调节剂（NAM）探针（ML289），该探针源自与之密切相关的 mGlu5 部分激动剂。
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3921-5. doi: 10.1016/j.bmcl.2012.04.112. Epub 2012 Apr 30.
3
Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists.发现 ADX-47273 型 mGlu5 PAM 骨架内的分子开关，这些开关调节药理学模式，从而产生强效的 mGlu5 NAMs、PAMs 和部分拮抗剂。
Bioorg Med Chem Lett. 2011 May 1;21(9):2711-4. doi: 10.1016/j.bmcl.2010.11.119. Epub 2010 Dec 3.
4
Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: unexpected 'molecular switch' from a closely related mGlu4 positive allosteric modulator.新型代谢型谷氨酸受体 4（mGlu4）拮抗剂的合成和 SAR 研究：来自密切相关的 mGlu4 正变构调节剂的意外“分子开关”。
Bioorg Med Chem Lett. 2011 Dec 1;21(23):6955-9. doi: 10.1016/j.bmcl.2011.09.131. Epub 2011 Oct 8.
5
Probing the metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology.探究代谢型谷氨酸受体 5（mGlu₅）正变构调节剂（PAM）结合口袋：发现导致 PAM 药理学中“分子开关”的点突变。
Mol Pharmacol. 2013 May;83(5):991-1006. doi: 10.1124/mol.112.083949. Epub 2013 Feb 26.
6
In vitro binding of a radio-labeled positive allosteric modulator for metabotropic glutamate receptor subtype 5.在体外与代谢型谷氨酸受体亚型 5 的正变构调节剂结合。
Synapse. 2013 Mar;67(3):135-44. doi: 10.1002/syn.21625. Epub 2012 Dec 6.
8
Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu(2)/mGlu(3) NAMs.作为双重亲代谢型谷氨酸受体2/3负变构调节剂的取代吡唑并[1,5-a]喹唑啉的合成与构效关系
Bioorg Med Chem Lett. 2014 Jun 15;24(12):2693-8. doi: 10.1016/j.bmcl.2014.04.051. Epub 2014 Apr 20.
9
Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.对代谢型谷氨酸受体1（mGlu₁）的正变构调节剂（PAM）Ro 07-11401骨架的重新探索：尽管结构活性关系（SAR）很陡峭，但仍发现了具有改善的中枢神经系统（CNS）渗透性的类似物。
Bioorg Med Chem Lett. 2016 May 1;26(9):2289-92. doi: 10.1016/j.bmcl.2016.03.044. Epub 2016 Mar 14.
10
Structure-based discovery and development of metabotropic glutamate receptor 5 negative allosteric modulators.基于结构的代谢型谷氨酸受体5负变构调节剂的发现与开发。
Adv Pharmacol. 2020;88:35-58. doi: 10.1016/bs.apha.2020.03.001. Epub 2020 Mar 25.
引用本文的文献
1
Acetylenic Replacement of Albicidin's Methacrylamide Residue Circumvents Detrimental E/Z Photoisomerization and Preserves Antibacterial Activity.炔基取代白利霉素甲丙烯酰胺残基可避免不利的 E/Z 光异构化并保持抗菌活性。
Chemistry. 2021 Jun 21;27(35):9077-9086. doi: 10.1002/chem.202100523. Epub 2021 May 21.
2
Allosteric Molecular Switches in Metabotropic Glutamate Receptors.变构分子开关在代谢型谷氨酸受体中的作用。
ChemMedChem. 2021 Jan 8;16(1):81-93. doi: 10.1002/cmdc.202000444. Epub 2020 Aug 25.
3
The mGlu antagonist LY-341,495 reverses the anti-dyskinetic and anti-psychotic effects of the mGlu activators LY-487,379 and LY-354,740 in the MPTP-lesioned marmoset.mGlu 拮抗剂 LY-341,495 逆转了 MPTP 损伤的狨猴中 mGlu 激动剂 LY-487,379 和 LY-354,740 的抗运动障碍和抗精神病作用。
J Neural Transm (Vienna). 2020 Jul;127(7):1013-1021. doi: 10.1007/s00702-020-02196-w. Epub 2020 Apr 24.
4
Evaluation of Synthetic Cytochrome P-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu Allosteric Ligands.用于促进一系列代谢型谷氨酸受体变构配体“仿生”生物转化的合成细胞色素P模拟金属卟啉的评估
ACS Omega. 2019 Jul 26;4(7):12782-12789. doi: 10.1021/acsomega.9b02017. eCollection 2019 Jul 31.
5
Recent advances in the medicinal chemistry of group II and group III mGlu receptors.II 型和 III 型代谢型谷氨酸受体药物化学的最新进展。
Medchemcomm. 2017 Jan 13;8(3):501-515. doi: 10.1039/c6md00612d. eCollection 2017 Mar 1.
6
Design and Synthesis of -Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu NAMs.作为高选择性且可穿透中枢神经系统的代谢型谷氨酸受体负性变构调节剂的芳基苯氧基乙氧基吡啶酮的设计与合成
ACS Med Chem Lett. 2017 Aug 15;8(9):925-930. doi: 10.1021/acsmedchemlett.7b00249. eCollection 2017 Sep 14.
7
Design and Synthesis of mGlu NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.基于截短的吡啶甲酰胺核心设计与合成具有更高效力和中枢神经系统渗透性的代谢型谷氨酸受体负变构调节剂
ACS Med Chem Lett. 2017 Aug 3;8(9):919-924. doi: 10.1021/acsmedchemlett.7b00279. eCollection 2017 Sep 14.
8
Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.GPCR变构调节剂发现中的实用策略与概念：代谢型谷氨酸受体的最新进展
Chem Rev. 2016 Jun 8;116(11):6707-41. doi: 10.1021/acs.chemrev.5b00656. Epub 2016 Feb 16.
9
Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2.4-氧代-1-芳基-1,4-二氢喹啉-3-甲酰胺作为代谢型谷氨酸受体亚型2的选择性负变构调节剂的设计
J Med Chem. 2015 Nov 25;58(22):9027-40. doi: 10.1021/acs.jmedchem.5b01371. Epub 2015 Nov 11.
10
Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents.发现一种对代谢型谷氨酸受体亚型3具有选择性且能穿透中枢神经系统的负变构调节剂，在啮齿动物中具有抗抑郁和抗焦虑活性。
J Med Chem. 2015 Sep 24;58(18):7485-500. doi: 10.1021/acs.jmedchem.5b01005. Epub 2015 Sep 10.
本文引用的文献
1
Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).朝向代谢型谷氨酸受体 5 型（mGluR5）的正变构调节剂的进展。
ACS Chem Neurosci. 2011 Aug 17;2(8):450-70. doi: 10.1021/cn2000519. Epub 2011 Jun 27.
2
Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.近期代谢型谷氨酸 4 受体配体鉴定的进展及其作为中枢神经系统治疗药物的潜在应用。
ACS Chem Neurosci. 2011 Aug 17;2(8):433-49. doi: 10.1021/cn200043e. Epub 2011 Jun 14.
3
Recent advances in the medicinal chemistry of the metabotropic glutamate receptor 1 (mGlu₁).代谢型谷氨酸受体 1（mGlu₁）的药物化学研究进展。
ACS Chem Neurosci. 2011 Aug 17;2(8):394-401. doi: 10.1021/cn2000124. Epub 2011 Mar 10.
4
Recent progress in the synthesis and characterization of group II metabotropic glutamate receptor allosteric modulators.近期 II 组代谢型谷氨酸受体变构调节剂的合成与表征研究进展。
ACS Chem Neurosci. 2011 Aug 17;2(8):382-93. doi: 10.1021/cn200008d. Epub 2011 Apr 12.
5
Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery.七跨膜受体的变构调节：理论、实践及中枢神经系统药物发现的机遇
J Med Chem. 2012 Feb 23;55(4):1445-64. doi: 10.1021/jm201139r. Epub 2012 Jan 6.
6
Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression.在抑郁症啮齿动物模型中对一种代谢型谷氨酸受体2/3负性变构调节剂的表征。
J Neurogenet. 2011 Dec;25(4):152-66. doi: 10.3109/01677063.2011.627485.
7
Recent advances in the design and development of novel negative allosteric modulators of mGlu(5).代谢型谷氨酸受体5（mGlu(5)）新型负变构调节剂设计与开发的最新进展
ACS Chem Neurosci. 2011 Aug 17;2(8):411-432. doi: 10.1021/cn2000266.
8
"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.调节药理学模式的 mGluR 变构配体上的“分子开关”。
Biochemistry. 2011 Apr 5;50(13):2403-10. doi: 10.1021/bi200129s. Epub 2011 Mar 4.
9
Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold.基于芳基乙炔双环内酰胺支架的中枢活性 mGlu5 正变构调节剂的合成及 SAR 研究。
Bioorg Med Chem Lett. 2011 Mar 1;21(5):1350-3. doi: 10.1016/j.bmcl.2011.01.044. Epub 2011 Jan 18.
10
Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective.针对与阿尔茨海默病相关的精神病的第二组代谢型谷氨酸(mGlu)受体治疗：在培养神经元中，选择性激活 mGlu2 受体放大β-淀粉样蛋白毒性，而 mGlu2 和 mGlu3 受体的双重激活具有神经保护作用。
Mol Pharmacol. 2011 Mar;79(3):618-26. doi: 10.1124/mol.110.067488. Epub 2010 Dec 15.
Zotero 插件