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.

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist was synthesized and studied for their affinity at M-M mAChRs. The 6-cyclohexyl-6-phenyl derivative , with a configuration between the CHN(CH) chain in the 2-position and the cyclohexyl moiety in the 6-position, showed p values for mAChRs higher than those of and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of and the corresponding tertiary amine revealed that the eutomers are (2,6)-(-)- and (2,6)-(-)-, respectively. Docking simulations on the M 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/M selectivity, which might limit cardiovascular side effects, make a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M receptors are involved.