TY  - JOUR
A1  - Volpato, Daniela
A1  - Kauk, Michael
A1  - Messerer, Regina
A1  - Bermudez, Marcel
A1  - Wolber, Gerhard
A1  - Bock, Andreas
A1  - Hoffmann, Carsten
A1  - Holzgrabe, Ulrike
T1  - The Role of Orthosteric Building Blocks of Bitopic Ligands for Muscarinic M1 Receptors
JF  - ACS Omega
N2  - The muscarinic M\(_1\) acetylcholine receptor is an important drug target for the treatment of various neurological disorders. Designing M\(_1\) receptor-selective drugs has proven challenging, mainly due to the high conservation of the acetylcholine binding site among muscarinic receptor subtypes. Therefore, less conserved and topographically distinct allosteric binding sites have been explored to increase M\(_1\) receptor selectivity. In this line, bitopic ligands, which target orthosteric and allosteric binding sites simultaneously, may provide a promising strategy. Here, we explore the allosteric, M1-selective BQCAd scaffold derived from BQCA as a starting point for the design, synthesis, and pharmacological evaluation of a series of novel bitopic ligands in which the orthosteric moieties and linker lengths are systematically varied. Since β-arrestin recruitment seems to be favorable to therapeutic implication, all the compounds were investigated by G protein and β-arrestin assays. Some bitopic ligands are partial to full agonists for G protein activation, some activate β-arrestin recruitment, and the degree of β-arrestin recruitment varies according to the respective modification. The allosteric BQCAd scaffold controls the positioning of the orthosteric ammonium group of all ligands, suggesting that this interaction is essential for stimulating G protein activation. However, β-arrestin recruitment is not affected. The novel set of bitopic ligands may constitute a toolbox to study the requirements of β-arrestin recruitment during ligand design for therapeutic usage.
KW  - muscarinic M1 receptor
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230548
VL  - 5
IS  - 49
ER  -