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

Journal of Medicinal Chemistry
2019.0

Abstract

Muscarinic acetylcholine receptors (MRs), comprising five subtypes (M<sub>1</sub>R-M<sub>5</sub>R) in humans, exhibit a high degree of structural similarity. Therefore, subtype-selective MR agonists and antagonists are lacking. We present an approach to highly M<sub>2</sub>R-selective MR antagonists based on the conjugation of di- or tripeptides to M<sub>2</sub>R-preferring dibenzodiazepinone-type MR antagonists. M<sub>2</sub>R selectivity was dependent on the peptide sequence and on the type of linker. The introduction of basic amino acids resulted in improved M<sub>2</sub>R selectivity (e.g., UR-AP148 (48): p K<sub>i</sub> (hM<sub>2</sub>R) of 8.97, ratio of K<sub>i</sub> M<sub>1</sub>R/M<sub>2</sub>R/M<sub>3</sub>R/M<sub>4</sub>R/M<sub>5</sub>R 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.

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