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Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M Receptor. | LitMetric

AI Article Synopsis

Article 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 MR affinities (p (radioligand competition binding): 9.10-9.59). Binding studies at M and M-M receptors indicated a MR preference. Flow cytometric and high-content imaging saturation and competition binding (MR, MR, and MR) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hMR cells). Results from dissociation and saturation binding experiments (MR) in the presence of allosteric MR 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 MR in imaging and binding studies and suggest that they have a dualsteric mode of action.

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http://dx.doi.org/10.1021/acs.jmedchem.9b02172DOI Listing

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