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Download fileRadiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M2 Muscarinic Acetylcholine Receptor
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posted on 2017-04-07, 00:00 authored by Andrea Pegoli, Xueke She, David Wifling, Harald Hübner, Günther Bernhardt, Peter Gmeiner, Max KellerThe dualsteric ligand approach, aiming
at ligands with improved
subtype selectivity, has been increasingly applied to muscarinic receptors
(MRs). In this article, we present the synthesis and characterization
of a M2R subtype-preferring radiolabeled dibenzodiazepinone-type
antagonist ([3H]UNSW-MK259, [3H]19) and its homodimeric analogue [3H]UR-AP060 ([3H]33). Saturation binding studies at the M2R, using the orthosteric antagonist atropine to determine unspecific
binding, proved that the monomeric and the dimeric compound bind to
the orthosteric binding site (apparent Kd: 0.87 and 0.31 nM, respectively). Various binding studies with [3H]19 and [3H]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 μs) performed with 19 and 33.
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allosteric MR modulators W 84orthosteric antagonist atropinedualsteric ligand approachVarious binding studiesSaturation binding studiesM 2 Muscarinic Acetylcholine ReceptorMDM 2 Rorthosteric binding site3 HLYdualsteric binding modedimeric compound bindsaturation binding experimentsRadiolabeled Dibenzodiazepinone-Type Antagonists