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Anticholinesterases
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
DFP and iso-OMPA selectively inhibit the plasma enzyme (BuchE), the former by 90% compared with only 20% of the erythrocyte AchE. DFP is highly permeant and can inactivate the intracellular compartment of cholinesterase. Parathion and malathion selectively inhibit the plasma enzyme, whereas others such as dimefox, mevinphos and the potent nerve agent, VX, initially inhibit the erythrocyte enzyme selectively (Sidell 1992). Selectivity among the ‘reversible’ inhibitors has also been reported, with bis(3-trimethylammonium-5-hydroxyphenoxyl) 1,3-propane (3116CT) being 250 000 times more potent against AchE than BuchE and 10-(1-diethylaminopropionyl) phenothiazine (Astra 1397) being 10 000 times more potent against the plasma enzyme (Bowman & Rand 1980). BW284c51 is a non-permeant selective inhibitor of AchE that inactivates only extracellular AchE (Atack et al. 1989); it also has some muscarinic blocking activity (Norel et al. 1993). Ethopropazine selectively inhibits BuchE (Massoulie et al. 1993, Vellom et al. 1993). These selective inhibitors have been used to demonstrate that BuchE has a role in the control of parasympathetic activity in tissues such as the airways. BW284c51 causes contraction of human isolated bronchial preparations whereas iso-OMPA does not, indicating that AchE is mainly responsible for degradation of endogenous Ach. However, iso-OMPA does potentiate the contractile effects of exogenous Ach. This indicates that BuchE, probably located in the smooth muscle, may have a secondary role to protect against an increased release of Ach or against the extraneuronal appearance of Ach (Norel et al. 1993).
Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ivana Šagud, Nikolina Maček Hrvat, Ana Grgičević, Tena Čadež, Josipa Hodak, Milena Dragojević, Kornelija Lasić, Zrinka Kovarik, Irena Škorić
The eleven new synthetised trans-amino-5-arylethenyl-oxazole derivatives (trans-2-trans-12, and trans-17) were tested in a wide concentration range as BChE inhibitors to evaluate the inhibitor concentration that inhibits 50% of enzyme activity (IC50), presented in Table 1. The most potent BChE inhibitors were compounds trans-12, trans-10 and trans-8 with an IC50 of about 30 µM. BChE had the lowest binding affinity for compound trans-11 which was 5.5-fold lower than the most potent inhibitor trans-12. It is interesting to note that the binding affinity of BChE for compounds trans-12, trans-10 and trans-8 was similar as reported for cholinesterase inhibitors BW284C51, huperzine or rivastigmine (IC50 30 – 54 µM)22.
Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease
Published in Xenobiotica, 2019
Ozlem Dalmizrak, Kerem Teralı, Osman Yetkin, I. Hamdi Ogus, Nazmi Ozer
Vertebrates have two different cholinesterases, namely acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8). Despite the fact that the two enzymes share 65% sequence homology, their substrate kinetics and behavior against inhibitors exhibit a considerable difference. For example, AChE is inhibited by high concentrations of acetylcholine (ACh), whereas BChE is activated by high concentrations of butyrylcholine (BCh) (Dave et al., 2000; Tougu, 2001; Masson et al., 2001). Another example is that AChE is selectively inhibited by 1,5-bis(4-allyldimethylaminopropyl)pentan-3-on dibromide (BW284C51), while BChE is selectively inhibited by isotetramonoisopropylpyrophosphatetetramid (iso-OMPA) and 10-[2-diethylaminopropyl]-phenothiazid (ethopropazine) (Radic et al., 1993). At molecular level, AChE and BChE are two distinct proteins encoded by two different but related genes: the gene for AChE is located on human chromosome 7q22, and the gene for BChE is located on chromosome 3q26 (Allderdice et al., 1991). The tissue distribution and localization of the two enzymes also show great variance. Although AChE is abundant in the membranes of the brain, muscle and erythrocytes, BChE has the highest activity in the heart, kidney, lung and intestines (Prody et al., 1987; Allderdice et al., 1991). Several species, including mice, horses and humans, demonstrate higher BChE activity than AChE activity in their serum, while rats have relatively high AChE activity in their serum (Ecobichon & Corneau, 1973; Prody et al., 1987; Chatonnet & Lockridge, 1989).
Toxicity of nanoplastics during the embryogenesis of the ascidian Ciona robusta (Phylum Chordata)
Published in Nanotoxicology, 2020
Maria Concetta Eliso, Elisa Bergami, Loredana Manfra, Antonietta Spagnuolo, Ilaria Corsi
C. robusta larvae were also tested for Cholinesterases (ChE) activity. At 22 hpf, embryos (1000 for each condition) were centrifuged at 600 × g for 15 min. The pellet was resuspended in 200 µL of homogenization buffer (20 mM Tris, 5 mM MgCl2, 0.1 mg mL−1 Bacitracin, 8 × 10−3 TIU ml−1 Aprotinin, 1% Triton X-100, pH 7.4) sonicated for 1 min at 6 cycles (power 10%) and then centrifuged at 8.400 × g (4 °C) for 20 min, according to the method of Corsi et al. (2007) with slight modifications as reported below. The supernatant was used for ChE enzymes activity assay according to the method of Ellman et al. (1961) adapted to microplate readers. Two thiocholine esters were used as substrates to gain information about the ChE type: acetylthiocholine iodide (ASCh) and butyrylthiocholine iodide (BSCh) as specific diagnostic substrates for Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) enzymes. Initial assay conditions in the reaction mixture (final volume 300 mL) were as follows: 0.1 M Na2PO4 (pH 7.2), 0.5 mM DTNB, 1 mM ChE substrates, embryos homogenate. The increase in absorbance at 405 nm was followed for 5 min at 20 °C using a 550 Model microplate reader (Bio-Rad). ChE enzymes activity was expressed in nmol per min per mg of protein: nmol min−1 mg protein−1. A selective AChE enzyme inhibitor, BW284c51, was tested at various concentrations (from 3.3 × 10−10 to 3.3 × 10−4 M) and incubated for 15 min with embryos homogenates and residual ChE vs ASCh activities and fifty percent inhibition concentration (IC50) values were determined. In order to evaluate the potential direct interaction of PS-NH2 with ChE vs ASCh activity, embryos extracts were also incubated with PS-NH2 suspensions at the following concentrations (2-7.5–10-15 µg mL−1) for 15 min, ASCh was then added to start the reaction and the activity was measured for 5 min following the same procedure described above. Total proteins were measured in embryos homogenates according to Bradford (1976) and values were expressed as mg protein mL−1 supernatant.