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Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-13 , DOI: 10.1021/acs.jmedchem.9b02172 Xueke She 1 , Andrea Pegoli 1 , Corinna G Gruber 1 , David Wifling 1 , Jessica Carpenter 2 , Harald Hübner 3 , Mengya Chen 1 , Jianfei Wan 1 , Günther Bernhardt 1 , Peter Gmeiner 3 , Nicholas D Holliday 2 , Max Keller 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-13 , DOI: 10.1021/acs.jmedchem.9b02172 Xueke She 1 , Andrea Pegoli 1 , Corinna G Gruber 1 , David Wifling 1 , Jessica Carpenter 2 , Harald Hübner 3 , Mengya Chen 1 , Jianfei Wan 1 , Günther Bernhardt 1 , Peter Gmeiner 3 , Nicholas D Holliday 2 , Max Keller 1
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Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indicated a M2R preference. Flow cytometric and high-content imaging saturation and competition binding (M1R, M2R, and M4R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM2R cells). Results from dissociation and saturation binding experiments (M2R) in the presence of allosteric M2R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M2R in imaging and binding studies and suggest that they have a dualsteric mode of action.
中文翻译：
发出红色的二苯并二氮杂醌衍生物，作为毒蕈碱型乙酰胆碱M2受体的荧光双空间探针。
荧光标记的二苯并二氮杂醌类毒蕈碱型乙酰胆碱受体（MR）拮抗剂（包括二聚体配体）是使用红色发光花菁染料制备的。含有带负电荷的荧光团的探针显示出较高的M2R亲和力（pKi（放射性配体竞争结合）：9.10-9.59）。在M1和M3-M5受体上的结合研究表明M2R偏好。流式细胞仪和高内涵成像饱和度和竞争结合（M1R，M2R和M4R）证实了正构位点的占据。共聚焦显微镜显示荧光主要位于细胞膜（CHO-hM2R细胞）处。在存在变构M2R调节剂的情况下进行解离和饱和结合实验（M2R）的结果（解离：W84，LY2119620和阿库溴铵；饱和结合：W84）与荧光探针和变构配体之间的竞争作用模式一致。综上所述，这些证据表明这些配体是有用的荧光分子工具，可在成像和结合研究中标记M2R，并表明它们具有双重立体作用模式。
更新日期：2020-04-24
中文翻译：
发出红色的二苯并二氮杂醌衍生物，作为毒蕈碱型乙酰胆碱M2受体的荧光双空间探针。
荧光标记的二苯并二氮杂醌类毒蕈碱型乙酰胆碱受体（MR）拮抗剂（包括二聚体配体）是使用红色发光花菁染料制备的。含有带负电荷的荧光团的探针显示出较高的M2R亲和力（pKi（放射性配体竞争结合）：9.10-9.59）。在M1和M3-M5受体上的结合研究表明M2R偏好。流式细胞仪和高内涵成像饱和度和竞争结合（M1R，M2R和M4R）证实了正构位点的占据。共聚焦显微镜显示荧光主要位于细胞膜（CHO-hM2R细胞）处。在存在变构M2R调节剂的情况下进行解离和饱和结合实验（M2R）的结果（解离：W84，LY2119620和阿库溴铵；饱和结合：W84）与荧光探针和变构配体之间的竞争作用模式一致。综上所述，这些证据表明这些配体是有用的荧光分子工具，可在成像和结合研究中标记M2R，并表明它们具有双重立体作用模式。
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