Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M-2 Muscarinic Acetylcholine Receptor

Journal article
(Original article)


Publication Details

Author(s): Pegoli A, She X, Wifling D, Hübner H, Bernhardt G, Gmeiner P, Keller M
Journal: Journal of Medicinal Chemistry
Publisher: AMER CHEMICAL SOC
Publication year: 2017
Volume: 60
Journal issue: 8
Pages range: 3314-3334
ISSN: 0022-2623


Abstract


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.



FAU Authors / FAU Editors

Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie


Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)


External institutions with authors

Universität Regensburg


How to cite

APA:
Pegoli, A., She, X., Wifling, D., Hübner, H., Bernhardt, G., Gmeiner, P., & Keller, M. (2017). Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M-2 Muscarinic Acetylcholine Receptor. Journal of Medicinal Chemistry, 60(8), 3314-3334. https://dx.doi.org/10.1021/acs.jmedchem.6b01892

MLA:
Pegoli, Andrea, et al. "Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M-2 Muscarinic Acetylcholine Receptor." Journal of Medicinal Chemistry 60.8 (2017): 3314-3334.

BibTeX: 

Last updated on 2018-10-08 at 21:29