Suppr超能文献

新型含 xanomeline 的毒蕈碱型乙酰胆碱受体双位点配体:设计、合成与荧光共振能量转移研究。

Novel Xanomeline-Containing Bitopic Ligands of Muscarinic Acetylcholine Receptors: Design, Synthesis and FRET Investigation.

机构信息

Department of Pharmaceutical Sciences, Medicinal Chemistry Section "Pietro Pratesi", University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy.

Institute for Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital Jena, Friedrich Schiller University Jena, Hans Knoell Str. 2, 07745 Jena, Germany.

出版信息

Molecules. 2023 Mar 6;28(5):2407. doi: 10.3390/molecules28052407.

Abstract

In the last few years, fluorescence resonance energy transfer (FRET) receptor sensors have contributed to the understanding of GPCR ligand binding and functional activation. FRET sensors based on muscarinic acetylcholine receptors (mAChRs) have been employed to study dual-steric ligands, allowing for the detection of different kinetics and distinguishing between partial, full, and super agonism. Herein, we report the synthesis of the two series of bitopic ligands, and and their pharmacological investigation at the M, M, M, and M FRET-based receptor sensors. The hybrids were prepared by merging the pharmacophoric moieties of the M/M-preferring orthosteric agonist Xanomeline and the M-selective positive allosteric modulator 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) . The two pharmacophores were connected through alkylene chains of different lengths (C3, C5, C7, and C9). Analyzing the FRET responses, the tertiary amine compounds , , and evidenced a selective activation of M mAChRs, while the methyl tetrahydropyridinium salts , , and showed a degree of selectivity for M and M mAChRs. Moreover, whereas hybrids showed an almost linear response at the M subtype, hybrids evidenced a bell-shaped activation response. This different activation pattern suggests that the positive charge anchoring the compound to the orthosteric site ensues a degree of receptor activation depending on the linker length, which induces a graded conformational interference with the binding pocket closure. These bitopic derivatives represent novel pharmacological tools for a better understanding of ligand-receptor interactions at a molecular level.

摘要

在过去的几年中,荧光共振能量转移(FRET)受体传感器促进了对 G 蛋白偶联受体(GPCR)配体结合和功能激活的理解。基于毒蕈碱乙酰胆碱受体(mAChR)的 FRET 传感器已被用于研究双重立体配体,允许检测不同的动力学并区分部分激动剂、完全激动剂和超激动剂。在此,我们报告了两个系列双位配体和的合成及其在基于 FRET 的 M、M、M 和 M 受体传感器上的药理学研究。这些杂种是通过合并 M/M 偏好的正构激动剂 Xanomeline 和 M 选择性正变构调节剂 77-LH-28-1(1-[3-(4-丁基-1-哌啶基)丙基]-3,4-二氢-2(1H)-喹啉酮)的药效团而制备的。两个药效团通过不同长度的亚乙基链(C3、C5、C7 和 C9)连接。通过分析 FRET 反应,叔胺化合物、和表现出对 M mAChR 的选择性激活,而甲基四氢吡啶盐、、和则表现出对 M 和 M mAChR 的一定程度的选择性。此外,尽管杂化物在 M 亚型上表现出几乎线性的响应,但杂化物则表现出钟形激活响应。这种不同的激活模式表明,将化合物锚定在正位点的正电荷会根据接头长度引发一定程度的受体激活,从而导致与结合口袋闭合的构象干扰呈分级变化。这些双位衍生物代表了更好地理解配体-受体相互作用的新型药理学工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e35/10005175/5ea2766c48e8/molecules-28-02407-g001.jpg

相似文献

3
Structural Features of Iperoxo-BQCA Muscarinic Acetylcholine Receptor Hybrid Ligands Determining Subtype Selectivity and Efficacy.
ACS Chem Neurosci. 2022 Jan 5;13(1):97-111. doi: 10.1021/acschemneuro.1c00572. Epub 2021 Dec 14.
4
FRET Studies of Quinolone-Based Bitopic Ligands and Their Structural Analogues at the Muscarinic M Receptor.
ACS Chem Biol. 2017 Mar 17;12(3):833-843. doi: 10.1021/acschembio.6b00828. Epub 2017 Feb 6.
5
Biased Profile of Xanomeline at the Recombinant Human M Muscarinic Acetylcholine Receptor.
ACS Chem Neurosci. 2022 Apr 20;13(8):1206-1218. doi: 10.1021/acschemneuro.1c00827. Epub 2022 Apr 5.
7
Orthosteric and allosteric modes of interaction of novel selective agonists of the M1 muscarinic acetylcholine receptor.
Mol Pharmacol. 2010 Jul;78(1):94-104. doi: 10.1124/mol.110.064345. Epub 2010 Apr 22.
8
FRET-based detection of M1 muscarinic acetylcholine receptor activation by orthosteric and allosteric agonists.
PLoS One. 2012;7(1):e29946. doi: 10.1371/journal.pone.0029946. Epub 2012 Jan 17.
9
Exploration of the orthosteric/allosteric interface in human M1 muscarinic receptors by bitopic fluorescent ligands.
Mol Pharmacol. 2013 Jul;84(1):71-85. doi: 10.1124/mol.113.085670. Epub 2013 Apr 19.
10
Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands.
BMC Pharmacol. 2009 Dec 2;9:14. doi: 10.1186/1471-2210-9-14.

本文引用的文献

1
Structural basis of efficacy-driven ligand selectivity at GPCRs.
Nat Chem Biol. 2023 Jul;19(7):805-814. doi: 10.1038/s41589-022-01247-5. Epub 2023 Feb 13.
3
The Role of Orthosteric Building Blocks of Bitopic Ligands for Muscarinic M1 Receptors.
ACS Omega. 2020 Dec 1;5(49):31706-31715. doi: 10.1021/acsomega.0c04220. eCollection 2020 Dec 15.
4
Ligand-Specific Allosteric Coupling Controls G-Protein-Coupled Receptor Signaling.
ACS Pharmacol Transl Sci. 2020 Sep 2;3(5):859-867. doi: 10.1021/acsptsci.0c00069. eCollection 2020 Oct 9.
5
Novel analgesic agents obtained by molecular hybridization of orthosteric and allosteric ligands.
Eur J Pharmacol. 2020 Jun 5;876:173061. doi: 10.1016/j.ejphar.2020.173061. Epub 2020 Mar 13.
7
Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M and M.
Medchemcomm. 2017 Apr 27;8(6):1346-1359. doi: 10.1039/c7md00149e. eCollection 2017 Jun 1.
9
Intramolecular and Intermolecular FRET Sensors for GPCRs - Monitoring Conformational Changes and Beyond.
Trends Pharmacol Sci. 2018 Feb;39(2):123-135. doi: 10.1016/j.tips.2017.10.011. Epub 2017 Nov 25.
10
Ligand-Specific Restriction of Extracellular Conformational Dynamics Constrains Signaling of the M Muscarinic Receptor.
ACS Chem Biol. 2017 Jul 21;12(7):1743-1748. doi: 10.1021/acschembio.7b00275. Epub 2017 Jun 12.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验