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 2 was synthesized and studied
for their affinity at M1–M5 mAChRs. The
6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in
the 6-position, showed pKi 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 (2S,6S)-(−)-3b and (2S,6S)-(−)-33b, respectively.
Docking simulations on the M3 mAChR-resolved structure
rationalized the experimental observations. The quaternary ammonium
function, which should prevent the crossing of the blood–brain
barrier, and the high M3/M2 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 M3 receptors are involved.

一系列新颖的1,4-二氧六环类毒蕈碱型乙酰胆碱受体(mAChR)拮抗剂2衍生物被合成并研究，以评估其在M1至M5 mAChR上的亲和力。其中，6-环己基-6-苯基衍生物3b，其2位的CH2N+(CH3)3链与6位的环己基部分之间具有顺式构型，显示出对mAChR的pKi值高于2，且选择性谱与已批准上市的药物氧丁宁相似。对3b和相应三级胺33b的外消旋体的研究揭示了外消旋体分别为(2S,6S)-(−)-3b和(2S,6S)-(−)-33b。在M3 mAChR解析结构上的对接模拟合理化了实验观察结果。四价铵功能团，其能够防止血液-脑屏障的穿透，以及高M3/M2选择性，可能限制心血管副作用，使得3b成为设计新型拮抗剂的有价值起点，这些新型拮抗剂可能对涉及M3受体的外周疾病具有潜在应用价值。