Ana-Marija Lulić , Lucija Marcelić , Alma Ramić , Andreja Radman Kastelic , Antonio Zandona , Nikola Maraković , Ines Primožič , Maja Katalinić
{"title":"胆碱酯酶活性调节剂:十二烷基氨基喹啉作为人乙酰胆碱酯酶和BChE抑制剂的评价。","authors":"Ana-Marija Lulić , Lucija Marcelić , Alma Ramić , Andreja Radman Kastelic , Antonio Zandona , Nikola Maraković , Ines Primožič , Maja Katalinić","doi":"10.1016/j.cbi.2025.111567","DOIUrl":null,"url":null,"abstract":"<div><div>In this study, we investigated the inhibitory activity of novel dodecylaminoquinuclidines (QAs) on neurotransmitter-hydrolyzing enzymes, specifically acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Following our previous findings, we modified the structure of a lead compound to develop more potent modulators of cholinesterase activity. The search for such inhibitors remains a key focus in the therapeutic management of organophosphate poisoning and various neurological disorders. For the design, we retained the aliphatic side linker and introduced various benzyl-based substituents to the quinuclidinium core, resulting in a set of 11 new compounds. All of these derivatives exhibited reversible inhibition of cholinesterase within the micromolar concentration range. The most significant factor affecting inhibition was the positional change of a specific group on the benzene ring, shifting from the <em>meta</em> to the <em>para</em> position. Specifically, analogues with groups in the <em>meta</em> position showed a stronger inhibition of AChE, whereas the <em>para</em> position was more effective for BChE. The most potent inhibitor featured a –CH<sub>3</sub> or -Br substituent, with a <em>K</em><sub>i</sub> of around 1.7–2.0 μM (<em>meta</em>-position) for AChE and 0.3–0.5 μM (<em>para</em>-position) for BChE. Additionally, we assessed the cytotoxicity of these compounds on human neuronal SH-SY5Y cells, as their intended target in the body. As all tested quinuclidine derivatives demonstrated a certain level of cytotoxicity within the range of 1.5–17 μM, further research is needed to explore this effect, and to validate or negate their potential for development into therapeutic agents.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111567"},"PeriodicalIF":4.7000,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cholinesterase activity modulators: Evaluation of dodecylaminoquinuclidines as inhibitors of human AChE and BChE\",\"authors\":\"Ana-Marija Lulić , Lucija Marcelić , Alma Ramić , Andreja Radman Kastelic , Antonio Zandona , Nikola Maraković , Ines Primožič , Maja Katalinić\",\"doi\":\"10.1016/j.cbi.2025.111567\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>In this study, we investigated the inhibitory activity of novel dodecylaminoquinuclidines (QAs) on neurotransmitter-hydrolyzing enzymes, specifically acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Following our previous findings, we modified the structure of a lead compound to develop more potent modulators of cholinesterase activity. The search for such inhibitors remains a key focus in the therapeutic management of organophosphate poisoning and various neurological disorders. For the design, we retained the aliphatic side linker and introduced various benzyl-based substituents to the quinuclidinium core, resulting in a set of 11 new compounds. All of these derivatives exhibited reversible inhibition of cholinesterase within the micromolar concentration range. The most significant factor affecting inhibition was the positional change of a specific group on the benzene ring, shifting from the <em>meta</em> to the <em>para</em> position. Specifically, analogues with groups in the <em>meta</em> position showed a stronger inhibition of AChE, whereas the <em>para</em> position was more effective for BChE. The most potent inhibitor featured a –CH<sub>3</sub> or -Br substituent, with a <em>K</em><sub>i</sub> of around 1.7–2.0 μM (<em>meta</em>-position) for AChE and 0.3–0.5 μM (<em>para</em>-position) for BChE. Additionally, we assessed the cytotoxicity of these compounds on human neuronal SH-SY5Y cells, as their intended target in the body. As all tested quinuclidine derivatives demonstrated a certain level of cytotoxicity within the range of 1.5–17 μM, further research is needed to explore this effect, and to validate or negate their potential for development into therapeutic agents.</div></div>\",\"PeriodicalId\":274,\"journal\":{\"name\":\"Chemico-Biological Interactions\",\"volume\":\"417 \",\"pages\":\"Article 111567\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-05-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemico-Biological Interactions\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0009279725001978\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-Biological Interactions","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0009279725001978","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Cholinesterase activity modulators: Evaluation of dodecylaminoquinuclidines as inhibitors of human AChE and BChE
In this study, we investigated the inhibitory activity of novel dodecylaminoquinuclidines (QAs) on neurotransmitter-hydrolyzing enzymes, specifically acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Following our previous findings, we modified the structure of a lead compound to develop more potent modulators of cholinesterase activity. The search for such inhibitors remains a key focus in the therapeutic management of organophosphate poisoning and various neurological disorders. For the design, we retained the aliphatic side linker and introduced various benzyl-based substituents to the quinuclidinium core, resulting in a set of 11 new compounds. All of these derivatives exhibited reversible inhibition of cholinesterase within the micromolar concentration range. The most significant factor affecting inhibition was the positional change of a specific group on the benzene ring, shifting from the meta to the para position. Specifically, analogues with groups in the meta position showed a stronger inhibition of AChE, whereas the para position was more effective for BChE. The most potent inhibitor featured a –CH3 or -Br substituent, with a Ki of around 1.7–2.0 μM (meta-position) for AChE and 0.3–0.5 μM (para-position) for BChE. Additionally, we assessed the cytotoxicity of these compounds on human neuronal SH-SY5Y cells, as their intended target in the body. As all tested quinuclidine derivatives demonstrated a certain level of cytotoxicity within the range of 1.5–17 μM, further research is needed to explore this effect, and to validate or negate their potential for development into therapeutic agents.
期刊介绍:
Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.