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ID: ALA4396879

Journal: J Med Chem

Title: Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines M₂R Selectivity.

Authors: Pegoli A, Wifling D, Gruber CG, She X, Hübner H, Bernhardt G, Gmeiner P, Keller M.

Abstract: Muscarinic acetylcholine receptors (MRs), comprising five subtypes (M₁R-M₅R) in humans, exhibit a high degree of structural similarity. Therefore, subtype-selective MR agonists and antagonists are lacking. We present an approach to highly M₂R-selective MR antagonists based on the conjugation of di- or tripeptides to M₂R-preferring dibenzodiazepinone-type MR antagonists. M₂R selectivity was dependent on the peptide sequence and on the type of linker. The introduction of basic amino acids resulted in improved M₂R selectivity (e.g., UR-AP148 (48): p K_i (hM₂R) of 8.97, ratio of K_i M₁R/M₂R/M₃R/M₄R/M₅R of 49:1:6500:60:400) compared to reported pyridobenzo- and dibenzodiazepinone-type MR ligands. A supposed dualsteric binding mode of the DIBA-peptide conjugates, such as 48, at MRs was supported by molecular dynamics simulations.

CiteXplore: 31074983

DOI: 10.1021/acs.jmedchem.8b01967