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Novel Xanomeline-Containing Bitopic Ligands of Muscarinic Acetylcholine Receptors: Design, Synthesis and FRET Investigation

ORCID
0000-0001-6939-3859
Affiliation
Department of Pharmaceutical Sciences, Medicinal Chemistry Section “Pietro Pratesi”, University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
Matera, Carlo;
Affiliation
Institute for Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital Jena, Friedrich Schiller University Jena, Hans Knoell Str. 2, 07745 Jena, Germany
Kauk, Michael;
ORCID
0000-0001-5133-0702
Affiliation
Department of Pharmaceutical Sciences, Medicinal Chemistry Section “Pietro Pratesi”, University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
Cirillo, Davide;
ORCID
0000-0002-2438-9490
Affiliation
Department of Pharmaceutical Sciences, Medicinal Chemistry Section “Pietro Pratesi”, University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
Maspero, Marco;
ORCID
0000-0003-1877-8331
Affiliation
Department of Pharmaceutical Sciences, Medicinal Chemistry Section “Pietro Pratesi”, University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
Papotto, Claudio;
Affiliation
Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Volpato, Daniela;
ORCID
0000-0002-0364-7278
Affiliation
Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Holzgrabe, Ulrike;
ORCID
0000-0002-0236-0662
Affiliation
Department of Pharmaceutical Sciences, Medicinal Chemistry Section “Pietro Pratesi”, University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
De Amici, Marco;
Affiliation
Institute for Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital Jena, Friedrich Schiller University Jena, Hans Knoell Str. 2, 07745 Jena, Germany
Hoffmann, Carsten;
ORCID
0000-0002-7383-1484
Affiliation
Department of Pharmaceutical Sciences, Medicinal Chemistry Section “Pietro Pratesi”, University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
Dallanoce, Clelia

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.

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