TY - JOUR
T1 - Design, synthesis and preclinical evaluation of muscarine receptor antagonists via a scaffold-hopping approach
AU - Millard, Marlon
AU - Kilian, Jonas
AU - Ozenil, Marius
AU - Mogeritsch, Mariella
AU - Schwingenschlögl-Maisetschläger, Verena
AU - Holzer, Wolfgang
AU - Hacker, Marcus
AU - Langer, Thierry
AU - Pichler, Verena
PY - 2023/12/15
Y1 - 2023/12/15
N2 - 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-hM
1-5 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 K
i-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 M
5, suggesting their prospective utility in positron emission tomography applications.
AB - 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-hM
1-5 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 K
i-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 M
5, suggesting their prospective utility in positron emission tomography applications.
KW - Muscarinic acetylcholine receptors
KW - Orthosteric binding site
KW - Pirenzepine
UR - http://www.scopus.com/inward/record.url?scp=85174813704&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2023.115891
DO - 10.1016/j.ejmech.2023.115891
M3 - Article
SN - 0223-5234
VL - 262
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 115891
ER -