Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M2 R Affinity and Selectivity

ACS Omega
Xueke SheMax Keller

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 (pKi > 8.3). The heterodimeric ligand UR-SK75 (46) exhibited the highest M2R affinity and selectivity [pKi (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 a...Continue Reading

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Citations

Dec 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Daniela Volpato, Ulrike Holzgrabe
Aug 9, 2019·International Journal of Molecular Sciences·Yutong SunHao Wang
Dec 22, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Lukas GrätzAgo Rinken

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Methods Mentioned

BETA
saturation binding
amidation
equilibrium competition binding
saturation-binding
nuclear magnetic resonance
NMR

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