Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

Abstract

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M ₁–M ₅ mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH ₂N ⁺(CH ₃) ₃ chain in the 2-position and the cyclohexyl moiety in the 6-position, showed p K _i values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2 S,6 S)-(−)- 3b and (2 S,6 S)-(−)- 33b, respectively. Docking simulations on the M ₃ mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood–brain barrier, and the high M ₃/M ₂ selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M ₃ receptors are involved.