Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M-2 Receptor
She X, Pegoli A, Gruber CG, Wifling D, Carpenter J, Hübner H, Chen M, Wan J, Bernhardt G, Gmeiner P, Holliday ND, Keller M (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 63
Pages Range: 4133-4154
Journal Issue: 8
DOI: 10.1021/acs.jmedchem.9b02172
Abstract
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 (pK(i) (radioligand competition binding): 9.10-9.59). Binding studies at M-1 and M-3-M-5 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-hM(2)R 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.
Authors with CRIS profile
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Involved external institutions
Germany (DE)
United Kingdom (GB)How to cite
APA:
She, X., Pegoli, A., Gruber, C.G., Wifling, D., Carpenter, J., Hübner, H.,... Keller, M. (2020). Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M-2 Receptor. Journal of Medicinal Chemistry, 63(8), 4133-4154. https://dx.doi.org/10.1021/acs.jmedchem.9b02172
MLA:
She, Xueke, et al. "Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M-2 Receptor." Journal of Medicinal Chemistry 63.8 (2020): 4133-4154.
BibTeX: Download