Acetylcholinesterase inhibitors properties

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... 

Nizri, E., Hanua-Amitay, Y., Sicsic, C., Lavon, L, Brenner, T. (2006). Anti-inflammatory properties of cholinergic up-regulation a new role for acetylcholinesterase inhibitors. Neuropharmacology 50 540-7. 

Yarowsky, R, Fowler, J.C., Taylor, G., and Weimeich, D., Noncholinesterase actions of an irreversible acetylcholinesterase inhibitor on synaptic transmission and membrane properties in autonomic ganglia. Cell. Molec. NeurobioL, 4, 351, 1984. 

P. is used in opthalmic practice in the same way as pilocarpine, for pupil contraction and for the reduction of intraocular pressure. It is an inhibitor of acetylcholinesterase, a property shared by certain other basic urethanes, such as neostigmine (prostigmine) these urethanes presumably acylate, and therefore block, the enzyme. P. and neostigmine have been used in surgery to counteract the action of curare, and both have been used for the relief of Myasthenia gravis, a disease characterized by muscular weakness associated with a rapid breakdown of acetylcholine. These have now been largely replaced by other synthetic compounds. 

In the other work [63], semi-empirical, restricted Hartree-Fock (RHF) and DFT calculations were carried out to study the well-known acetylcholinesterase inhibitors tacrine (32), galantamine (33), donepezil (34), tacrine dimer (35), and physo-stigmine (36). Some electronic and structural properties were evaluated (Table 7.3),... 

Table 10.4 Pharmacological properties of selected acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer s disease... 

Galantamine is a reversible inhibitor of acetylcholinesterase that also possesses nicotinic receptor agonist properties, and which is used in mild-to-moderate dementia in Alzheimer s disease. 

Individual cholinesterase inhibitors differ in their selectivity, mechanism of inhibition of acetylcholinesterase (Schneider 2001), and pharmacokinetic properties (outlined in Table 7-2). 

Pancreatic cholesterol esterase (3.1.1.3.) aids in transporting cholesterol to the enterocyte. By utilizing a selective and potent cholesterol esterase inhibitor 6-chloro-3-(l-ethyl-2-cyclohexyl)-2-pyrone, the absorption of cholesterol in hamsters could be reduced [71]. Wadkins et al. [72] synthesized novel sulfonamide derivatives, which demonstrated greater than 200-fold selectivity for human intestinal carboxylesterase compared with the human liver carboxylesterase hCEl, and none of them was an inhibitor of human acetylcholinesterase or butyrylcholinester-ase. Maybe these agents can serve as lead compounds for the development of effective, selective carboxylesterase inhibitors for clinical applications. Also the potent P-gp inhibitor verapamil [73] as well as S,S,S-tributylphosphortrithionate (DEF) [74] may exhibit carboxylesterase inhibitory properties. Various other inhibitors of human esterases are listed in Table 5.6. 

Memoquin is a quinone-bearing polyamine compound which acts as an acetylcholinesterase and p-secretase-1 inhibitor, and also possesses antiamyloid and antioxidant properties [580]. 

In similar studies, we have compared the toxicity of the same carbamate insecticide to several laboratory animal species that varied considerably insofar as rates of in vitro ester hydrolysis was concerned. Again, it was the more susceptible species which demonstrated the faster rates of hydrolysis (6). Neither absorption from the gut, or total metabolism as evidenced by excretion rates and metabolites excreted, was significantly different when the same carbamate was administered to either rats, mice, guinea pigs, or gerbils. At this point, it can only be surmised that the same properties that make the carbamates excellent in vivo inhibitors of acetylcholinesterase also make them excellent substrates for other esterases. 

More elegant analytical methods exploit substances biological or biochemical properties. This is simple for acetylcholinesterase-inhibiting pesticides. Acetylcholinesterase is easy to measure, and the enzyme may be bought from suppliers or extracted from flies, earthworms, or vertebrate nervous tissue. The enzyme may be measured with and without addition of the extract containing the insecticide. Some plant materials may contain natural cholinesterase inhibitors (e.g., solanine in potato) that will interfere with this analysis if not removed. 

The pro-cholinergic effect by inhibition of acetylcholinesterase has been proven, but is not the only action of these compounds (Table 1.4). In their review of the subject, Wagstaff and McTavish [1] discussed the therapeutic potential of the different properties of tacrine and recalled that it is impossible to attribute the clinically observed phenomena exclusively to one or other of this drug s properties. Certain features would suggest there is a possible cytoprotector action (anti-glutamate effect [166, 167], an MAO inhibitor effect and a cytoskeleton effect) associated with the symptomatic effect currently in the limelight resulting from the action initially described for neurotransmitters. 

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