Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M2R Affinity and Selectivity

Xueke She; Andrea Pegoli; Judith Mayr; Harald Hübner; Günther Bernhardt; Peter Gmeiner; Max Keller

doi:10.1021/acsomega.7b01085

Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M₂R Affinity and Selectivity

ACS Omega. 2017 Oct 31;2(10):6741-6754. doi: 10.1021/acsomega.7b01085. Epub 2017 Oct 16.

Authors

Xueke She¹, Andrea Pegoli¹, Judith Mayr¹, Harald Hübner², Günther Bernhardt¹, Peter Gmeiner², Max Keller¹

Affiliations

¹ Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany.
² Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstr. 19, D-91052 Erlangen, Germany.

Abstract

In search for selective ligands for the muscarinic acetylcholine receptor (MR) subtype M₂, the dimeric ligand approach, that is combining two pharmacophores in one and the same molecule, was pursued. Different types (agonists, antagonists, orthosteric, and allosteric) of monomeric MR ligands were combined by various linkers with a dibenzodiazepinone-type MR antagonist, affording five types of heterodimeric compounds ("DIBA-xanomeline," "DIBA-TBPB," "DIBA-77-LH-28-1," "DIBA-propantheline," and "DIBA-4-DAMP"), which showed high M₂R affinities (pK_i > 8.3). The heterodimeric ligand UR-SK75 (46) exhibited the highest M₂R affinity and selectivity [pK_i (M₁R-M₅R): 8.84, 10.14, 7.88, 8.59, and 7.47]. Two tritium-labeled dimeric derivatives ("DIBA-xanomeline"-type: [³H]UR-SK71 ([³H]44) and "DIBA-TBPB"-type: [³H]UR-SK59 ([³H]64)) were prepared to investigate their binding modes at hM₂R. Saturation-binding experiments showed that these compounds address the orthosteric binding site of the M₂R. The investigation of the effect of various allosteric MR modulators [gallamine (13), W84 (14), and LY2119620 (15)] on the equilibrium (13-15) or saturation (14) binding of [³H]64 suggested a competitive mechanism between [³H]64 and the investigated allosteric ligands, and consequently a dualsteric binding mode of 64 at the M₂R.