Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M-2 Muscarinic Acetylcholine Receptor
Pegoli A, She X, Wifling D, Hübner H, Bernhardt G, Gmeiner P, Keller M (2017)
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2017
Journal
Publisher: AMER CHEMICAL SOC
Book Volume: 60
Pages Range: 3314-3334
Journal Issue: 8
DOI: 10.1021/acs.jmedchem.6b01892
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.
Authors with CRIS profile
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Additional Organisation(s)
Involved external institutions
Germany (DE)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.
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