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Keywords = bambuterol

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14 pages, 3333 KiB  
Article
Rivastigmine–Bambuterol Hybrids as Selective Butyrylcholinesterase Inhibitors
by Jie Wu, Zekai Tan, Marco Pistolozzi and Wen Tan
Molecules 2024, 29(1), 72; https://doi.org/10.3390/molecules29010072 - 22 Dec 2023
Cited by 3 | Viewed by 2142
Abstract
Selective butyrylcholinesterase inhibitors are considered promising drug candidates for the treatment of Alzheimer’s disease. In this work, one rivastigmine–bambuterol hybrid (MTR-1) and fourteen of its analogues were synthesized, purified, and characterized. In vitro cholinesterase assays showed that all the compounds were more potent [...] Read more.
Selective butyrylcholinesterase inhibitors are considered promising drug candidates for the treatment of Alzheimer’s disease. In this work, one rivastigmine–bambuterol hybrid (MTR-1) and fourteen of its analogues were synthesized, purified, and characterized. In vitro cholinesterase assays showed that all the compounds were more potent inhibitors of BChE when compared to AChE. Further investigations indicated that MTR-3 (IC50(AChE) > 100,000 nM, IC50(BChE) = 78 nM) was the best compound in the series, showing high butyrylcholinesterase selectivity and inhibition potency, the potential to permeate the blood–brain barrier, and longer-lasting BChE inhibition than bambuterol. These compounds could be used to discover novel specific BChE inhibitors for the treatment of Alzheimer’s disease. Full article
(This article belongs to the Special Issue Synthesis and Evaluation of Bioactivity of Enzyme Inhibitors)
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19 pages, 42917 KiB  
Article
Enhancement of Fear Extinction Memory and Resistance to Age-Related Cognitive Decline in Butyrylcholinesterase Knockout Mice and (R)-Bambuterol Treated Mice
by Weiwei Liu, Yan Cao, Yue Lin, Keai Sinn Tan, Haishan Zhao, Haihua Guo and Wen Tan
Biology 2021, 10(5), 404; https://doi.org/10.3390/biology10050404 - 5 May 2021
Cited by 7 | Viewed by 3695
Abstract
Butyrylcholinesterase (BChE) is detected in plaques preferentially in Alzheimer’s disease (AD) and may be associated with stress disorders. However, the physiological function of BChE in the central nervous system remains to be further investigated. BChE knockout (KO) mice and wild-type (WT) mice with [...] Read more.
Butyrylcholinesterase (BChE) is detected in plaques preferentially in Alzheimer’s disease (AD) and may be associated with stress disorders. However, the physiological function of BChE in the central nervous system remains to be further investigated. BChE knockout (KO) mice and wild-type (WT) mice with orally or intranasal administration of (R)-bambuterol were used to explore the effect of BChE on behavior changes. (R)-bambuterol is a specific and reversible inhibitor of BChE. The behavior changes were evaluated and compared among 3–10 month old mice. Our finding showed that BChE KO and (R)-bambuterol administration enhanced episodic memory, including fear conditioning memory and fear extinction memory in fear conditioning and fear extinction test. BChE KO and (R)-bambuterol administered mice rescued age-related spatial memory and general activity in the water maze test and open field test. The brain metabolomics were imaged using a desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The image of DESI-MS demonstrated that glutamine content increased in the brain of BChE KO mice. In conclusion, this study found that inhibition of BChE ameliorated episodic and spatial memories. This study also suggested that (R)-bambuterol as a BChE inhibitor has the potential application in the treatment of post-traumatic stress disorder (PTSD) and early cognitive decline. Full article
(This article belongs to the Section Behavioural Biology)
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15 pages, 2008 KiB  
Article
Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates
by Anita Bosak, Aljoša Bavec, Tilen Konte, Goran Šinko, Zrinka Kovarik and Marko Goličnik
Molecules 2020, 25(1), 211; https://doi.org/10.3390/molecules25010211 - 4 Jan 2020
Cited by 9 | Viewed by 3964
Abstract
Mammalian paraoxonase-1 hydrolyses a very broad spectrum of esters such as certain drugs and xenobiotics. The aim of this study was to determine whether carbamates influence the activity of recombinant PON1 (rePON1). Carbamates were selected having a variety of applications: bambuterol and physostigmine [...] Read more.
Mammalian paraoxonase-1 hydrolyses a very broad spectrum of esters such as certain drugs and xenobiotics. The aim of this study was to determine whether carbamates influence the activity of recombinant PON1 (rePON1). Carbamates were selected having a variety of applications: bambuterol and physostigmine are drugs, carbofuran is used as a pesticide, while Ro 02-0683 is diagnostic reagent. All the selected carbamates reduced the arylesterase activity of rePON1 towards the substrate S-phenyl thioacetate (PTA). Inhibition dissociation constants (Ki), evaluated by both discontinuous and continuous inhibition measurements (progress curves), were similar and in the mM range. The rePON1 displayed almost the same values of Ki constants for Ro 02-0683 and physostigmine while, for carbofuran and bambuterol, the values were approximately ten times lower and two times higher, respectively. The affinity of rePON1 towards the tested carbamates was about 3–40 times lower than that of PTA. Molecular modelling of rePON1-carbamate complexes suggested non-covalent interactions with residues of the rePON1 active site that could lead to competitive inhibition of its arylesterase activity. In conclusion, carbamates can reduce the level of PON1 activity, which should be kept in mind, especially in medical conditions characterized by reduced PON1 levels. Full article
(This article belongs to the Special Issue Enzymes Reacting with Organophosphorus Compounds)
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