Acetylcholinesterase structure-activity relationship

Kang SY, Lee KY, Sung SH, Park MJ, Kim YC, Coumarins isolated from Angelica gigas inhibit acetylcholinesterase Structure-activity relationships, f Nat Prod 64 683-685,2001. 

The cholinesterases, acetylcholinesterase and butyrylcholinesterase, are serine hydrolase enzymes. The biological role of acetylcholinesterase (AChE, EC 3.1.1.7) is to hydrolyze the neurotransmitter acetylcholine (ACh) to acetate and choline (Scheme 6.1). This plays a role in impulse termination of transmissions at cholinergic synapses within the nervous system (Fig. 6.7) [12,13]. Butyrylcholinesterase (BChE, EC 3.1.1.8), on the other hand, has yet not been ascribed a function. It tolerates a large variety of esters and is more active with butyryl and propio-nyl choline than with acetyl choline [14]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in their specificity with respect to the acyl moiety of the substrate [15]. AChE hydrolyzes ACh at a very high rate. The maximal rate for hydrolysis of ACh and its thio analog acetyl-thiocholine are around 10 M s , approaching the diffusion-controlled limit [16]. 

This area is a development in the usage of NDDO models that emphasizes their utility for large-scale problems. Structure-activity relationships (SARs) are widely used in the pharmaceutical industry to understand how the various features of biologically active molecules contribute to their activity. SARs typically take the form of equations, often linear equations, that quantify activity as a function of variables associated with the molecules. The molecular variables could include, for instance, molecular weight, dipole moment, hydrophobic surface area, octanol-water partition coefficient, vapor pressure, various descriptors associated with molecular geometry, etc. For example, Cramer, Famini, and Lowrey (1993) found a strong correlation (r = 0.958) between various computed properties for 44 alkylammonium ions and their ability to act as acetylcholinesterase inhibitors according to the equation... 

H. Sugimoto, Structure activity relationships of acetylcholinesterase inhibitors done-pezil hydrochloride for the treatment of Alzheimer s Disease, Pure Appl. Chem. 71 (1999) 2031-2037. 

Rival RM, Wermuth CG. Design, synthesis and structure-activity relationships of a series of 3-[2-(l-benzylpiperi-din-4-yl)ethylamino]pyridazine derivatives as acetylcholinesterase inhibitors. 

Chen YL, et al. Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors 8-carbaphysostigmine analogues./. Med. Chem., 1992, 35(8), 1429-1434. 

In contrast to acetylcholinesterase, which is selective for acetylcholine, butyryl-cholinesterase tolerates a wider variety of esters and is more active with butyryl-and propionylcholines than acetylcholine [7]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in specificity to the acyl moiety of the substrate [6]. 

Ali HM, Sharaf EHA, Hikal MS. Selectivity, acetylcholinesterase inhibition kinetics and quantitative structure-activity relationships of a series of N-(2-oxido-l,3,2-benzodioxa-phosphol-2-yl) amino acid ethyl or diethyl esters. Pest Biochem Physiol 2005 83 58-65. 

Lin G, Lai CY, Liao WC. Molecular recognition by acetylcholinesterase at the peripheral anionic site Structure-activity relationships for inhibitions by aryl carbamates. Bioorg Med Chem 1999 7 2683-9. 

Sugimoto, H., limura, Y, Yamanishi, Y, Yamatsu, K. Synthesis and structure—activity relationships of acetylcholinesterase inhibitors l-benzyl-4-[(5,6-dimethoxy-l-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds. J. Med. Chem, 1996, 38, 4821 829. 

Chen, Y. L., Nielsen, J., Hedberg, K. D., Dunaiskis, A., Jones, S., Russo, L., Johnson, J., Ives, J., Liston, D. Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors 898-carbaphysostigmine analogues. J. Med. Chem. 1992, 35, 1429-1434. 

Contreras, J. M., Parrot, I., Sippl, W., Rival, Y. M., Wermuth, C. G. Design, synthesis, and structure-activity relationships of a series of 3-[2-(l-benzylpiperidin-4-yl)ethylamino]pyridazine derivatives as acetylcholinesterase inhibitors. J. Med. Chem. 2001, 44(17), 2707-2718. 

Mary, A., Renko, D. Z., Guillou, C., Thai, C. Potent acetylcholinesterase inhibitors design, synthesis, and structure-activity relationships of te-interacting ligands in the galanthamine series. Bioorg. Med. Chem. 1998, 6, 1835-1850. 

Toda, N., Tago, K., Marumoto, S., Takami, K., Ori, M., Yamada, N., Koyama, K., Naruto, S., Abe, K., Yamazaki, R., Hara, T, Aoyagi, A., Abe, Y, Kaneko, T, Kogen, H. Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer s disease. Bioorg. Med. Chem. 2003, 11, 1935-1955. 

Dimoglo, A.S., Shvets, N.M., Telko, l.V. and Livingstone, D.J. (2001) Electronic-topological investigation of the structure-acetylcholinesterase inhibitor activity relationship in the series of N-benzylpiperidine derivatives. Quant. Struct. -Act. Relat., 20, 31—45. 

Su C-T, Wang P-H, Liu R-F et al. (1986). Kinetic studies and structure-activity relationships of bispyridinium oximes as reactivators of acetylcholinesterase inhibited by organophosphorus compounds. Fund Appl Toxicol, 6, 506-524. 

A thorough understanding of the structure-activity relationships of these compounds has led to an ability to enhance their desired pharmacodynamic effects while minimizing unwanted or harmful adverse effects. The impact of the application of this knowledge is multifaceted for the clinician. Examples include the synthesis of newer chemical compounds used to treat Alzheimer s disease that provide greater affinity for acetylcholinesterase in the brain than in the periphery, decrease the frequency of dosing required, and alleviate the risk... 

A. Goldblum, M. Yoshimoto, and C. Hansch, ]. Agric. Food Chem., 29,277 (1981). Quantitative Structure-Activity Relationship of Phenyl N-Methylcarbamate Inhibition of Acetylcholinesterase. 

Through studies of the structure-activity relationship of the phosphoramidate derivatives, a new insecticide and nematicide, IKI-1145, (RS)-S-sec-butyl-0-ethyl-2-oxo-l,3-thiazolidin-3-y1-phosphorothioate, was discovered. This agent is characterized by marked nematicidal effects and systemic activity against various pests. Optical resolution of IKI-1145 was carried out by using preparative HPLC. On in vitro examination, both isomers are found to be poor inhibitors of acetylcholinesterase. On the other hand, against various pests, (-)-IKI-1145 is more active than (+)-isomer, from about twenty-fold to thirty-fold, implying selective metabolic activation by pest species. 

Arning, J., Stolte, S., Boschen, A., Stock, R, Pimer, W.R., Welz-Biermann, U, Jastorff, B. and Ranke, J., Qualitative and quantitative structure activity relationships for the inhibitory effects of cationic head groups, functionalised side chains and anions of ionic liquids on acetylcholinesterase. Green Chem. 10, 47-58 (2008). 

Ruark, C.D., Hack, C.E., Robinson, P.J., et al, 2013. Quantitative structure-activity relationships for organophosphates binding to acetylcholinesterase. Arch. 

Carbamates - Structure activity relationships have been studied with respect to toxicity and anticholinesterase activity. 9 The mechanism of acetylcholinesterase inhibition by the carbamates is not entirely clear. 

The great majority of insecticides are nerve poisons. The target for most of them is an enzyme called acetylcholinesterase (AChE). We will describe the enzyme and its inhibition in some detail because there are no other enzymes for which we know so much about the relationship between its structure and its activity. The cholinesterase-inhibiting insecticides, the warfare gases, and the target enzyme have been the objects of intense study by scientists for many years. 

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