毒蕈碱型M <sub>1</sub>受体的喹诺酮类双配体及其结构类似物的FRET研究,ACS Chemical Biology

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毒蕈碱型M ₁受体的喹诺酮类双配体及其结构类似物的FRET研究
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-02-06 00:00:00 , DOI: 10.1021/acschembio.6b00828
Regina Messerer ₁ , Michael Kauk _{2,

3} , Daniela Volpato ₁ , Maria Consuelo Alonso Canizal _{2,

3} , Jessika Klöckner ₁ , Ulrike Zabel _{2,

3} , Susanne Nuber _{2,

3} , Carsten Hoffmann _{2,

3} , Ulrike Holzgrabe ₁

Affiliation

为了设计M ₁毒蕈碱型乙酰胆碱（M ₁ AChR）受体的部分激动剂和变构调节剂，设计并合成了两个不同系列的双药效配体及其结构类似物。杂种由苄基喹诺酮羧酸（BQCA）衍生的亚型选择性变构调节剂3和正构构筑物4-（（4,5-dihydroisoxazol-3-yl）oxy）-N，N-methylbut-2-组成分别是yn-1-胺（petrorox的碱）1或内源性配体2-（二甲基氨基）乙酸乙酯（乙酰胆碱的碱）2。这两个药效团通过不同长度（C4，C6，C8和C10）的亚烷基链。此外，1和2以及修饰的BQCA 3的相应结构类似物研究了在C2和C10之间具有不同烷基链长度的化合物。为了了解这些化合物如何在分子水平上与G蛋白偶联受体（GPCR）相互作用以及单个部分如何促进配体受体相互作用，研究了在活的单细胞系统中进行的荧光共振能量转移（FRET）测量。修饰的正构配体的表征表明，连接至正构的连接基迅速减弱了受体反应。接头长度的延长会增加双位配体的受体反应，直至达到最大值，然后逐渐降低。发现最佳接头长度为在M ₁处为六个亚甲基。AChR。描述了一种新的构象变化，该构象变化不是长连接位双向配体的反向激动起源，并且已通过基于例外片段的筛选方法进行了进一步研究。

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FRET Studies of Quinolone-Based Bitopic Ligands and Their Structural Analogues at the Muscarinic M1 Receptor

Aiming to design partial agonists as well as allosteric modulators for the M₁ muscarinic acetylcholine (M₁AChR) receptor, two different series of bipharmacophoric ligands and their structural analogues were designed and synthesized. The hybrids were composed of the benzyl quinolone carboxylic acid (BQCA)-derived subtype selective allosteric modulator 3 and the orthosteric building block 4-((4,5-dihydroisoxazol-3-yl)oxy)-N,N-dimethylbut-2-yn-1-amine (base of iperoxo) 1 or the endogenous ligand 2-(dimethylamino)ethyl acetate (base of acetylcholine) 2, respectively. The two pharmacophores were linked via alkylene chains of different lengths (C4, C6, C8, and C10). Furthermore, the corresponding structural analogues of 1 and 2 and of modified BQCA 3 with varying alkyl chain length between C2 and C10 were investigated. Fluorescence resonance energy transfer (FRET) measurements in a living single cell system were investigated in order to understand how these compounds interact with a G protein-coupled receptor (GPCR) on a molecular level and how the single moieties contribute to ligand receptor interaction. The characterization of the modified orthosteric ligands indicated that a linker attached to an orthoster rapidly attenuates the receptor response. Linker length elongation increases the receptor response of bitopic ligands, until reaching a maximum, followed by a gradual decrease. The optimal linker length was found to be six methylene groups at the M₁AChR. A new conformational change is described that is not of inverse agonistic origin for long linker bitopic ligands and was further investigated by exceptional fragment-based screening approaches.

更新日期：2017-02-06

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