TY  - JOUR
A1  - Matera, Carlo
A1  - Kauk, Michael
A1  - Cirillo, Davide
A1  - Maspero, Marco
A1  - Papotto, Claudio
A1  - Volpato, Daniela
A1  - Holzgrabe, Ulrike
A1  - De Amici, Marco
A1  - Hoffmann, Carsten
A1  - Dallanoce, Clelia
T1  - Novel Xanomeline-containing bitopic ligands of muscarinic acetylcholine receptors: design, synthesis and FRET investigation
JF  - Molecules
N2  - In the last few years, fluorescence resonance energy transfer (FRET) receptor sensors have contributed to the understanding of GPCR ligand binding and functional activation. FRET sensors based on muscarinic acetylcholine receptors (mAChRs) have been employed to study dual-steric ligands, allowing for the detection of different kinetics and distinguishing between partial, full, and super agonism. Herein, we report the synthesis of the two series of bitopic ligands, 12-Cn and 13-Cn, and their pharmacological investigation at the M\(_1\), M\(_2\), M\(_4\), and M\(_5\) FRET-based receptor sensors. The hybrids were prepared by merging the pharmacophoric moieties of the M\(_1\)/M\(_4\)-preferring orthosteric agonist Xanomeline 10 and the M\(_1\)-selective positive allosteric modulator 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) 11. The two pharmacophores were connected through alkylene chains of different lengths (C3, C5, C7, and C9). Analyzing the FRET responses, the tertiary amine compounds 12-C5, 12-C7, and 12-C9 evidenced a selective activation of M\(_1\) mAChRs, while the methyl tetrahydropyridinium salts 13-C5, 13-C7, and 13-C9 showed a degree of selectivity for M\(_1\) and M\(_4\) mAChRs. Moreover, whereas hybrids 12-Cn showed an almost linear response at the M\(_1\) subtype, hybrids 13-Cn evidenced a bell-shaped activation response. This different activation pattern suggests that the positive charge anchoring the compound 13-Cn to the orthosteric site ensues a degree of receptor activation depending on the linker length, which induces a graded conformational interference with the binding pocket closure. These bitopic derivatives represent novel pharmacological tools for a better understanding of ligand-receptor interactions at a molecular level.
KW  - muscarinic acetylcholine receptors
KW  - Xanomeline
KW  - 77-LH-28-1
KW  - bitopic hybrid ligands
KW  - synthesis
KW  - fluorescence resonance energy transfer
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311249
SN  - 1420-3049
VL  - 28
IS  - 5
ER  -