Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol

Bosak, Anita; Gazić, Ivana; Vinković, Vladimir; Kovarik, Zrinka

doi:10.1016/j.abb.2007.12.007

Cited by 11 publications

(11 citation statements)

References 13 publications

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“…The peripheral site of AChE consists of Tyr72, Tyr124, Asp74, Tyr341, and Trp286, while Tyr332 and Asp70 are considered as BChE peripheral site [8,14]. Differences in amino acid composition at the CAS and PAS dictate the selectivity of compounds, such as phosphonates, acetates, alcohols, and carbamates [8,[15][16][17][18][19], for either cholinesterase. The AChE PAS is involved in the formation of the stable AChE-Aß complex that is more toxic than age-related Aß peptide aggregates [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer’s Disease

et al. 2022

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Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimer’s disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new structurally distinct 4-aminoquinolines bearing an adamantane moiety. Inhibition studies revealed that all of the compounds were very potent inhibitors of AChE and butyrylcholinesterase (BChE), with inhibition constants (Ki) ranging between 0.075 and 25 µM. The tested compounds exhibited a modest selectivity between the two cholinesterases; the most selective for BChE was compound 14, which displayed a 10 times higher preference, while compound 19 was a 5.8 times more potent inhibitor of AChE. Most of the compounds were estimated to be able to cross the blood–brain barrier (BBB) by passive transport. Evaluation of druglikeness singled out fourteen compounds with possible oral route of administration. The tested compounds displayed modest but generally higher antioxidant activity than the structurally similar AD drug tacrine. Compound 19 showed the highest reducing power, comparable to those of standard antioxidants. Considering their simple structure, high inhibition of AChE and BChE, and ability to cross the BBB, 4-aminoquinoline-based adamantanes show promise as structural scaffolds for further design of novel central nervous system drugs. Among them, two compounds stand out: compound 5 as the most potent inhibitor of both cholinesterases with a Ki constant in low nano molar range and the potential to cross the BBB, and compound 8, which met all our requirements, including high cholinesterase inhibition, good oral bioavailability, and antioxidative effect. The QSAR model revealed that AChE and BChE inhibition was mainly influenced by the ring and topological descriptors MCD, Nnum, RP, and RSIpw3, which defined the shape, conformational flexibility, and surface properties of the molecules.

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Section: Introductionmentioning

confidence: 99%

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer’s Disease

et al. 2022

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“…The active site of BChE differs in six out of the 14 aromatic residues lining AChE, which have aliphatic residues on corresponding places in BChE [16,18,19]. These differences lead to different interactions with the same substrates and ligands and defined AChE and BChE specificity and selectivity [20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase

Bosak

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Šinko

et al. 2019

Chemico-Biological Interactions

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Eight derivatives of 4-aminoquinolines differing in the substituents attached to the C(4)amino group and C(7) were synthesised and tested as inhibitors of human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Both enzymes were inhibited by all of the compounds with inhibition constants (K i ) ranging from 0.50 to 50 µM exhibiting slight selectivity toward AChE over BChE. The most potent inhibitors of AChE were compounds with an n-octylamino chain or adamantyl group. The shortening of the chain length resulted in a decrease in AChE inhibition by 5-20 times. Docking studies revealed that the quinoline group within the AChE active site was positioned in the choline binding site, while the C(4)amino group substituents, depending on their lipophilicity, could establish hydrogen bonds or π-interactions with residues of the peripheral anionic site. The most potent inhibitors of BChE were compounds with the most voluminous substituent on C(4)-amino group (adamantyl) or those with a stronger electron withdrawing the substituent on C(7) (trifluormethyl group).Based on AChE inhibition, compounds with an n-octylamino chain or adamantyl substituent were shown to possess the capacity for further development as potential drugs for treatment of neurodegenerative diseases.

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“…; Bosak et al. ). Because bambuterol is also a beta 2 adrenergic receptor ( β 2AR) agonist, we assessed the protein level of β 2AR in atrial tissues, which was low and unchanged in HFD, as mentioned above.…”

Section: Resultsmentioning

confidence: 97%

“…Thus, we tested whether the elevated BChE level may have any role in the reduced vagal control of heart rate in HFD mice. Bambuterol's inhibitory effect on BChE activity has been well documented (Sinko et al 2005;Bosak et al 2008). Because bambuterol is also a beta 2 adrenergic receptor (b2AR) agonist, we assessed the protein level of b2AR in atrial tissues, which was low and unchanged in HFD, as mentioned above.…”

Section: Effect Of Bche Activity Inhibition On Psns Functionmentioning

confidence: 99%

Reduced vagal control of the heart in high-fat diet mice: a potential role of increased butyrylcholinesterase

et al. 2015

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Suppressed parasympathetic function is commonly present in cardiovascular diseases, aging, obesity, and various other health conditions. Impaired parasympathetic action is known as a detrimental factor and contributes to the adverse outcomes in these conditions. However, the underlying mechanisms remain to be fully addressed. In this study, using high-fat diet (HFD)-induced obese mice as a model, the potential peripheral mechanisms underlying the impaired parasympathetic vagal control of the heart was examined. The HFD induced obesity and metabolic disorder in mice. These obese mice exhibited an attenuated response in heart rate to vagal stimulation, indicating impairment of peripheral parasympathetic activity in the heart. In cholinergic function-related proteins in the atria, protein levels of choline transporter and vesicular acetylcholine transporter were not decreased but increased, and type 2 muscarinic receptors showed a trend toward a reduction in HFD mice atria as compared with regular diet (RD) mice controls. While the protein level of acetylcholinesterase was not different, butyrylcholinesterase (BChE) protein level showed a twofold increase in HFD mice atria as compared with RD mice. Functionally, inhibition of BChE activity partially and significantly improved the attenuated response in heart rate to vagal stimulation in HFD mice. Collectively, these data suggest that increased BChE activity in the atria may contribute to the decreased parasympathetic function in HFD-induced obese mice.

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Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol

Cited by 11 publications

References 13 publications

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer’s Disease

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer’s Disease

Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase

Reduced vagal control of the heart in high-fat diet mice: a potential role of increased butyrylcholinesterase

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