Butyrylcholinesterase inhibitors

Rivastigmine 40% 1.5 None anticipated Not hepatically metabolized (metabolized by hydrolysis and renally eliminated) Dual acetylcholinesterase and butyrylcholinesterase inhibitor... 

Cholinesterase inhibitor (acetylcholinesterase inhibitor and butyrylcholinesterase inhibitor) cognitive enhancer... 

A new series of acetophenone derivatives which possess alkyl-amine side chains were designed, synthesized, and assayed as acetylcholinesterase and butyrylcholinesterase inhibitors [183],... 

Nadri H, Pirali-Hamedani M, Moradi A, Sakhteman A, Vahidi A, Sheibani V et al (2013) 5,6-Dimethoxybenzofuran-3 -one derivatives A novel series of dual Acetylcholinesterase/ Butyrylcholinesterase inhibitors bearing benzyl pyridinium moiety. Darn 21 15... 

Csuk R, Albert S, Kluge R, Strohl D (2013) Resverattol derived butyrylcholinesterase inhibitors. Arch Pharm (Weinheim) 346 499-503... 

Lin Z, Wang H, Fu Q, An H, Liang Y, Zhang B et al (2013) Simultaneous separation, identification and activity evaluation of three butyrylcholinesterase inhibitors from Plumula nelumbinis using on-line HPLC-UV coupled... 

Clayton and Purcell have illustrated the predictive utility of this method when applied to selected butyrylcholinesterase inhibitors (94). They obtained quantitative correlations using group dipole moments, and /x in addition to hydrophobic parameters. In addition, Hansch and co-workers have used Taft steric parameters (Es) (60) and pKa values to obtain excellent correlations in various systems (84). E8 has recently been shown to be quantitatively related to van der Waal s radii for symmetrical top-like substituents (98) while pKa values have been used as a measure of electron density distributions (99). Fukuto and co-workers combined Tafts Es and a parameters in a physicochemical approach to the mode of action of organophosphorus insecticides (95). 

Kamal MA, Qu X, Yu Q-S, Tweedie D, Holloway HW, Li Y, Tan Y, Greig NH (2008) Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis. J Neural Transm 115 889-898... 

Butyryl-choline detection in such a system can be realized by two different coupling approaches (i) co-immobilization of butyrylcholinesterase on a choline bienzyme electrode, which results in a tri-enzyme electrochemical sensing system (ii) use of solubilized butyrylcholinesterase in a coupled system with an electrode for choline determination, by addition of standard amounts of the dissolved enzyme to the measuring cell. In both cases butyrylcholinesterase activity affects the choline electrode response providing the presence of choline in the solution. Both coupling approaches are suitable for analysis of butyrylcholinesterase inhibitors such as organophosphorus compounds. 

Rivera-Becerril, E Joseph-Nathan, P., Perez-Alvarez, V.M., and Morales-Rios, M.S. (2008) Synthesis and biological evaluation of (-)-and (-F)-debromoflustramine B and its analogues as selective butyrylcholinesterase inhibitors./. Med. Chem., 51, 5271-5284. 

Galanthamine (23) is an alkaloid extracted from the common snowdrop Galanthus nivalis. This compound is a long-acting, competitive AChE inhibitor which appears to be somewhat more specific for acetylcholinesterase than plasma butyrylcholinesterase (132). It is well tolerated during long-term treatment (133) and is being evaluated clinically for AD (134). 

Metrifonate [52-68-6] (24) is itself not an AChE inhibitor, but is none2ymaticaIly converted into an active irreversible inhibitor of the en2yme. The compound is relatively specific for AChE over butyrylcholinesterase (135) and the irreversible nature of its inhibition gives rise to an extended duration of action. Some clinical experience has been gained through its use to treat schistosomiasis (136,137) and it is undergoing clinical evaluation for AD. 

The dual inhibition of acetylcholinesterase and butyrylcholinesterase may lead to broader efficacy. As acetylcholinesterase activity decreases with disease progression, the acetylcholinesterase-selective agents may lose their effect, while the dual inhibitors may still be effective due to the added inhibition of butyrylcholinesterase. However, this has not been demonstrated clinically. 

Giacobini, E. (ed.) Butyrylcholinesterase its Function and Inhibitors. London Martin Dunitz, 2003. 

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

S. J. Gatley, Activities of the Enantiomers of Cocaine and Some Related Compounds as Substrates and Inhibitors of Plasma Butyrylcholinesterase , Biochem. Pharmacol. 1991, 41, 1249-1254. 

Decker M, Novel inhibitors of acetyl- and butyrylcholinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine, Eur J Med Chem 40 305-313,... 

Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase). Flowever, inhibition of butyrylcholinesterase plays little role in the action of indirect-acting cholinomimetic drugs because this enzyme is not important in the physiologic termination of synaptic acetylcholine action. Some quaternary cholinesterase inhibitors also have a modest direct action as well, eg, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase. 

FIGURE 12—24. Icon for the cholinesterase inhibitor donepezil. This is the current first-line treatment for Alzheimer s disease, since it is a once daily agent without significant hepatotoxicity. It is a reversible agent, selective for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE), developed by American and Japanese companies. 

FIGURE 12-25. Icon for the cholinesterase inhibitor tacrine. This was the first cholinesterase inhibitor, but since it is a hepatoxotin, it has been relegated to second-line use. Also, it must be given four times daily, is difficult to dose, and has several drug interactions. It is short-acting, reversible, and nonselective, inhibiting both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). 

Which of the following cholinesterase inhibitors is selective for acetylcholinesterase over butyrylcholinesterase ... 

Arisugacin not only demonstrates impressive potency in inhibiting AChE with an IC50 value of 1 nM, but more importantly, it is highly selective for AChE since >18 flM is required to inhibit butyrylcholinesterase [BuChE], In contrast, tacrine and other inhibitors are less selective for AChE. In the case of tacrine, it is actually more selective for BuChE with an IC50 value of 12 nM, thereby raising concerns about its potential in liver damage.13... 

Donepezil HC1, a piperidine, is a highly selective inhibitor of the enzyme AChE [3,4] that is chemically unique from other AChE inhibitors [5, 6]. In vitro and preclinical studies have demonstrated that donepezil is approximately 1200 times more selective for AChE in the brain than for butyrylcholinesterase (BuChE) in the periphery [3, 4, 7]. Phase II and III studies conducted in the United States have shown that donepezil (5 or 10 mg once daily) produces statistically significant improvements in cognition and global function in patients with AD [8-10]. Its clinical efficacy and minimal side-effect profile are thought to be related to its specific inhibition of AChE in the areas of the brain affected by the cholinergic deficit that typifies this disease [3, 4, 7],... 

Oxazocine 119 is a synthetic derivative of galanthamine 162. The latter is a tertiary alkaloid, isolated from amaryllidaceae, which is a central acting competitive and reversible inhibitor of acetylcholinesterase that enhances cognitive functions in Alzheimer s patients. However, oxazocine 119 showed a decreased potency as an acetylcholinesterase inhibitor and a marked selectivity with respect to butyrylcholinesterase, probably because butyrylcholinesterase accommodates steric bulk around the catalytic site, better than acetylcholinesterase <2003BML2389>. 

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