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

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]. T

SUBMITTER: She X 

PROVIDER: S-EPMC6044897 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature