She, Xueke and Pegoli, Andrea and Gruber, Corinna G. and Wifling, David and Carpenter, Jessica and Huebner, Harald and Chen, Mengya and Wan, Jianfei and Bernhardt, Guenther and Gmeiner, Peter and Holliday, Nicholas D. and Keller, Max (2020) Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M-2 Receptor. JOURNAL OF MEDICINAL CHEMISTRY, 63 (8). pp. 4133-4154. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOLECULAR-DYNAMICS SIMULATIONS; ALLOSTERIC AGONIST TBPB; HISTAMINE H-2-RECEPTOR; LIGAND-BINDING; NEUROPEPTIDE-Y; PHARMACOLOGICAL-ACTIVITY; GPCR LIGANDS; M1; ANTAGONISTS; AFFINITY; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2021 11:22 |
| Last Modified: | 26 Mar 2021 11:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44710 |
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