Acetylcholinesterase AchE Inhibitor

Exposure to nerve agents is not restricted to the battlefield. Possible terrorist use of these weapons and the destruction of the chemical weapon depots certainly will increase the risk of exposure. Since treatment for intoxication with at least some of these organophosphorus (OP) acetylcholinesterase (AChE) inhibitors is still far from ideal, research efforts are devoted towards finding an effective treatment. 

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

Donepezil hydrochloride (E2020) is the second drug approved by the US FDA for the treatment of mild to moderate Alzheimer s diseases (AD). It is a new class of acetylcholinesterase (AChE) inhibitor having an... 

In another report, several acetylcholinesterase (AChE) inhibitors, including tacrine, edrophonium, tetramethyl- and tetraethyl-ammonium chloride, carbofu-ran, and eserine were assayed on a chip [1045]. AChE converted the substrate, acetylthiocholine, to thiocholine. This product reacted with coumarinylphenyl-maleimide (CPM) to form thiocholine-CPM (a thioether) for LIF detection. Since the acetonitrile solvent used to dissolve CPM inhibited AChE activity, the CPM solution was added after the enzymatic reaction [1045]. Another enzyme inhibition assay using a peptide substrate was performed on a PMMA chip [1046]. 

A new strategy in drug discovery, the selective optimization of side activities (the SOSA approach), has been formulated by Camille Wermuth [17,18 cf. Chapter I—1], In this approach, minor side activities of active compounds serve as the starting point for structural variations, ultimately to obtain analogues that now have the former side effect as their main activity. In this manner, nanomolar acetylcholinesterase (AChE) inhibitors as well as nanomolar muscarinic M, receptor and 5-HT3 receptor ligands could be derived from the antidepressant minaprine [17,18],... 

Figure 2.23 Minaprine 83 (Figure 2.22) is also a weak acetylcholinesterase (AChE) inhibitor (K, AChE = 600 pM). Optimization of this side activity to deoxo,demethyl-minaprine 87 (Kt AChE = 13 pM) and an isomeric N-benzyl-piperazine 88 (K, AChE = 120 nM) finally resulted in the potent AChE inhibitor 89 (K, AChE = 10 nM). 

Braginskaya F. 1., Molochkina E. M., Zorina O. M. et al. New synthetic bioantioxidants - acetylcholinesterase (AChE) inhibitors, in Alzheimer Disease From Molecular Biology to Therapy. R. Becker and E. Giacobini (eds.). Birkhauser-Boston. 1996, 337-342. 

Myasthenia gravis is treated with acetylcholinesterase (AChE inhibitors) ... 

NP-9 is a monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitor. NP-9 inhibits AChE activity and Ap aggregation, and protects against scopolamine and Ap 2-induced memory impairments [168]. 

Acetylcholinesterase (AChE) inhibitors are successfully used as drugs for the treatment of Alzheimer s disease. Physostigmine, also named eserine, has been isolated from the Calabar bean Physostigmina Venenosum). It is classified as a pseudo-irreversible inhibitor because it reacts with acetyl- as well as butyryl-cholinesterase (BChE) to form a carbamylated serine which is hydrolyzed again with a fi/2 of 40 min [73]. Physostigmine inhibits AChE with an IC50 of 27.9 nM and BChE with an IC50 of 16 nM. Its enantiomer is 350 times less active on AChE and 150 times less active on BchE [74]. 

Alzheimer s disease is associated with a progressive loss of cholinergic neurons in the brain that results in memory disturbances and cognitive dysfunction. One strategy for the treatment of Alzheimer s patients has been the use of acetylcholinesterase (AChE) inhibitors such as rivastigmine to enhance choUnergic activity in the central nervous system,... 

Further, continuous studies on S. pulmonaria by Tadesse and coworkers isolated two more new alkaloids pulmonarins A (19) and B (20) (Figure 2) [15]. The structures were determined as dibrominated quaternary ammonium salts by spectroscopic methods and confirmed by their synthesis as well. They found acetylcholinesterase (AChE) inhibitors and the most active inhibitor was pulmonarin B (20) with the inhibition constant value of 20 pM [15]. 

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