TY - JOUR
T1 - New potent muscarinic receptor ligands bearing the 1,4-dioxane nucleus
T2 - Investigation on the nature of the substituent in position 2
AU - Giorgioni, Gianfabio
AU - Bonifazi, Alessandro
AU - Matucci, Rosanna
AU - Matteucci, Federica
AU - Piergentili, Alessandro
AU - Piergentili, Alessia
AU - Quaglia, Wilma
AU - Gervasoni, Silvia
AU - Vistoli, Giulio
AU - Vittorio, Serena
AU - Del Bello, Fabio
N1 - Publisher Copyright:
© 2024 Deutsche Pharmazeutische Gesellschaft.
PY - 2024/10
Y1 - 2024/10
N2 - A new series of muscarinic acetylcholine receptor (mAChR) ligands obtained by inserting different substituents in position 2 of the potent 6,6-diphenyl-1,4-dioxane antagonists 4 and 5 was designed and synthesized to investigate the influence of steric bulk on the mAChR affinity. Specifically, the insertion of a 2-methyl group, affording compounds 6 and 9, resulted as the most favorable modification in terms of affinity for all muscarinic subtypes. As supported by computational studies performed on the hM1 receptor, this substituent may contribute to stabilize the ligand within the binding site by favoring the formation of stable interactions between the cationic head of the ligand and the residue D105. The increase of steric bulk, obtained by replacing the methyl group with an ethyl (7 and 10) and especially a phenyl substituent (8 and 11), caused a marked decrease of mAChR affinity, demonstrating the crucial role played by the steric bulk of the 2-substituent in the mAChR interaction. The most intriguing result was obtained with the tertiary amine 9, which, surprisingly, showed two different pKi values for all mAChRs, with preferential subpicomolar affinities for the M1, M3, and M4 subtypes. Interestingly, biphasic curves were also observed with both the eutomer (S)-(–)-9 and the distomer (R)-(+)-9.
AB - A new series of muscarinic acetylcholine receptor (mAChR) ligands obtained by inserting different substituents in position 2 of the potent 6,6-diphenyl-1,4-dioxane antagonists 4 and 5 was designed and synthesized to investigate the influence of steric bulk on the mAChR affinity. Specifically, the insertion of a 2-methyl group, affording compounds 6 and 9, resulted as the most favorable modification in terms of affinity for all muscarinic subtypes. As supported by computational studies performed on the hM1 receptor, this substituent may contribute to stabilize the ligand within the binding site by favoring the formation of stable interactions between the cationic head of the ligand and the residue D105. The increase of steric bulk, obtained by replacing the methyl group with an ethyl (7 and 10) and especially a phenyl substituent (8 and 11), caused a marked decrease of mAChR affinity, demonstrating the crucial role played by the steric bulk of the 2-substituent in the mAChR interaction. The most intriguing result was obtained with the tertiary amine 9, which, surprisingly, showed two different pKi values for all mAChRs, with preferential subpicomolar affinities for the M1, M3, and M4 subtypes. Interestingly, biphasic curves were also observed with both the eutomer (S)-(–)-9 and the distomer (R)-(+)-9.
KW - 6,6-diphenyl-1,4-dioxane derivatives
KW - biphasic curves in binding assays
KW - computational studies
KW - muscarinic receptor ligands
KW - subpicomolar mAChR affinity
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U2 - 10.1002/ardp.202400337
DO - 10.1002/ardp.202400337
M3 - Article
AN - SCOPUS:85199874753
SN - 0365-6233
VL - 357
JO - Archiv der Pharmazie
JF - Archiv der Pharmazie
IS - 10
M1 - e2400337
ER -