Pegoli, Andrea and She, Xueke and Wifling, David and Huebner, Harald and Bernhardt, Guenther and Gmeiner, Peter and Keller, Max (2017) Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M-2 Muscarinic Acetylcholine Receptor. JOURNAL OF MEDICINAL CHEMISTRY, 60 (8). pp. 3314-3334. ISSN 0022-2623, 1520-4804
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The dualsteric ligand approach, aiming at ligands with improved subtype selectivity, has been increas-X ingly applied to muscarinic receptors (MRs). In this article, we present the synthesis and characterization of a M2R subtype preferring radiolabeled dibenzodiazepinone-type antagonist ([H-3]UNSW-MK259, [H-3]19) and its homodimeric analogue [H-3]UR-AP060 ([H-3]33). Saturation binding studies at the M2R, using the orthosteric antagonist atropine to determine unspecific binding, proved that the monomeric and the dinieric compound bind to the orthosteric binding site (apparent Kd: 0.87 and 0.31 nM, respectively). Various binding studies with [H-3]19 and [H-3]33 at the M2R, for instance, saturation binding-experiments in the presence of the allosteric MR modulators W84 (8) or LY2119620 (9) (Schild-like analysis) suggested a competitive mechanism between the allosteric modulator and the dibenzodiazepinone derivatives, and thus a dualsteric binding mode of both 19 and 33. This was consistent with the results of M2R MD simulations (>= 2 mu s) performed with 19 and 33.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOLECULAR-DYNAMICS SIMULATIONS; GENERAL FORCE-FIELD; PROTEIN-COUPLED RECEPTORS; ALLOSTERIC MODULATORS; ALZHEIMERS-DISEASE; LIGAND-BINDING; NEUROPEPTIDE-Y; RESIDENCE TIME; CNS DISORDERS; CHARMM; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:10 |
| Last Modified: | 20 Feb 2019 07:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1011 |
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