Titel
Design, synthesis and preclinical evaluation of muscarine receptor antagonists via a scaffold-hopping approach
Autor*in
Marius Ozenil
Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna
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Abstract
Our research group recently identified a rearrangement product of pirenzepine as starting point for a comprehensive rational drug design approach towards orthosteric muscarinic acetylcholine receptor ligands. Chemical reduction and bioscaffold hop lead to the development of sixteen promising compounds featuring either a benzimidazole or carbamate moiety, all exhibiting comparable pharmacophoric characteristics. The synthesized compounds were characterized by NMR, HR-MS, and RP-HPLC techniques. Subsequent evaluation encompassed binding affinity assessment on CHO-hM1-5 cells, mode of action determination, and analysis of physico-chemical parameters. The CNS MPO score indicated favorable drug-like attributes and potential CNS activity for the antagonistic ligands. The most promising compounds displayed Ki-values within a desirable low nanomolar range, and their structural features allow for potential carbon-11 radiolabeling. Our optimization efforts resulted in compounds with a remarkable 138-fold increase in binding affinity compared to the previously mentioned rearrangement product towards human M5, suggesting their prospective utility in positron emission tomography applications.
Stichwort
Muscarinic acetylcholine receptorsPirenzepineOrthosteric binding site
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
European Journal of Medicinal Chemistry
Band
262
ISSN
0223-5234
Erscheinungsdatum
2023
Publication
Elsevier BV
Erscheinungsdatum
2023
Zugänglichkeit
Rechte
Rechteangabe
© 2023 The Authors
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