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

Beitrag in einer Fachzeitschrift
(Originalarbeit)


Details zur Publikation

Autor(en): Pegoli A, She X, Wifling D, Hübner H, Bernhardt G, Gmeiner P, Keller M
Zeitschrift: Journal of Medicinal Chemistry
Verlag: AMER CHEMICAL SOC
Jahr der Veröffentlichung: 2017
Band: 60
Heftnummer: 8
Seitenbereich: 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-Autoren / FAU-Herausgeber

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


Zusätzliche Organisationseinheit(en)
Emil-Fischer-Zentrum (Emil Fischer Center)


Autor(en) der externen Einrichtung(en)
Universität Regensburg


Zitierweisen

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: 

Zuletzt aktualisiert 2018-10-08 um 21:29