Effect of hexyloxy position on antagonistic properties of KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) at muscarinic acetylcholine receptors

IF 6.9 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Biomedicine & Pharmacotherapy Pub Date : 2025-03-14 DOI:10.1016/j.biopha.2025.117977
Alena Janoušková-Randáková , Eva Mezeiová , Jana Bláhová , Nikolai Chetverikov , Eva Dolejší , Dominik Nelic , Lukáš Prchal , Martin Novák , Jan Korábečný , Jan Jakubík
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Abstract

Antagonists with a long residence time at the receptors are desired for the possibility of reducing daily doses and side effects. KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) is the long-acting M1-preferring bitopic muscarinic antagonist with a half-life at muscarinic receptors of up to five hours. The binding of 2-hexyloxy and 3-hexyloxy analogues of KH-5 was simulated in silico, compounds were synthesized and their binding and antagonistic properties were measured experimentally in CHO cells expressing individual subtypes of muscarinic acetylcholine receptors. The overall binding affinities of the new compounds were similar to their respective parent compounds. Shifting the hexyloxy chain to ortho and meta positions led to a decrease in potency at the M1 receptor but an increase in potency at the M2 receptor and abolition of long-term antagonism. Preservation of the para position of the hexyloxy chain is essential for the further development of M1-preferring antagonists. Modifications of the basic centre may be the way to improve the geometry of antagonists towards long residence times to obtain the desired long-acting muscarinic antagonists in the future. The additional challenge for further development is the low metabolic stability of compounds.
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己氧基位置对 KH-5(1-{2-[4-(己氧基)苯甲酰氧基]乙基}-1-甲基-1,2,3,6-四氢吡啶-1-鎓碘化物)在毒蕈碱乙酰胆碱受体上拮抗特性的影响
人们希望拮抗剂在受体上的停留时间较长,以减少每日剂量和副作用。KH-5(1-{2-[4-(己氧基)苯甲酰氧基]乙基}-1-甲基-1,2,3,6-四氢吡啶-1-鎓碘化物)是长效的 M1 首选位毒蕈碱拮抗剂,在毒蕈碱受体的半衰期长达 5 小时。我们对 KH-5 的 2-hexyloxy 和 3-hexyloxy 类似物的结合进行了硅模拟,合成了化合物,并在表达各亚型毒蕈碱乙酰胆碱受体的 CHO 细胞中对其结合和拮抗特性进行了实验测定。新化合物的总体结合亲和力与各自的母体化合物相似。将羟基链转移到正位和偏位会导致对 M1 受体的效力下降,但对 M2 受体的效力上升,并消除长期拮抗作用。保留羟基链的对位对于进一步开发 M1 首选拮抗剂至关重要。对基本中心进行修改可能是改善拮抗剂几何形状、延长其停留时间的方法,从而在未来获得所需的长效毒蕈碱类拮抗剂。进一步开发的另一个挑战是化合物的低代谢稳定性。
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来源期刊
CiteScore
11.90
自引率
2.70%
发文量
1621
审稿时长
48 days
期刊介绍: Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.
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