Dibenzodiazepinone-type muscarinic receptor antagonists conjugated to basic peptides: Impact of the linker moiety and unnatural amino acids on M 2 R selectivity.

The family of human muscarinic acetylcholine receptors (MRs) is characterized by a high sequence homology among the five subtypes (M ₁ R-M ₅ R), being the reason for a lack of subtype selective MR ligands. In continuation of our work on dualsteric dibenzodiazepinone-type M ₂ R antagonists, a series of M ₂ R ligands containing a dibenzodiazepinone pharmacophore linked to small basic peptides was synthesized (64 compounds). The linker moiety was varied with respect to length, number of basic nitrogens (0-2) and flexibility. Besides proteinogenic basic amino acids (Lys, Arg), shorter homologues of Lys and Arg, containing three and two methylene groups, respectively, as well as D-configured amino acids were incorporated. The type of linker had a marked impact on M ₂ R affinity and also effected M ₂ R selectivity. In contrast, the structure of the basic peptide rather determined M ₂ R selectivity than M ₂ R affinity. For example, the most M ₂ R selective compound (UR-CG188, 89) with picomolar M ₂ R affinity (pK _i 9.60), exhibited a higher M ₂ R selectivity (ratio of K _i M ₁ R/M ₂ R/M ₃ R/M ₄ R/M ₅ R: 110:1:5200:55:2300) compared to the vast majority of reported M ₂ R preferring MR ligands. For selected ligands, M ₂ R antagonism was confirmed in a M ₂ R miniG protein recruitment assay.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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