Cholinesterase inhibitors, specific

Organophosphorus nerve agents are potent cholinesterase inhibitors, specifically acetylcholinesterase (AChE), the... 

Cholinesterases (ChEs), polymorphic carboxyles-terases of broad substrate specificity, terminate neurotransmission at cholinergic synapses and neuromuscular junctions (NMJs). Being sensitive to inhibition by organophosphate (OP) poisons, ChEs belong to the serine hydrolases (B type). ChEs share 65% amino acid sequence homology and have similar molecular forms and active centre structures [1]. Substrate and inhibitor specificities classify ChEs into two subtypes ... 

Donepezil is a piperidine cholinesterase inhibitor, which reversibly and non-competitively inhibits centrally active acetylcholinesterase 34 This specificity is claimed to result in fewer peripheral side effects as compared to the other ChE inhibitors. 

The causes of death in these studies were not specifically mentioned, but disulfoton is a cholinesterase inhibitor, and animals exposed to disulfoton typically exhibit cholinergic signs of toxicity (see Section 2.2.2.4). 

Currently the only specific pharmacological therapeutic option available for AD patients is treatment with cholinesterase inhibitors, which provide moderate benefits in a subset of patients for a limited period [7]. More efficient future therapeutic strategies may be directed at the metabolic events resulting in Ap accumulation, for example by inhibition of P- or y-sec-retase [7], or at the prevention of neuronal loss by neurotrophin therapy [6]. The availability of transgenic mouse models of the disease, such as mice overexpressing APP mutants [8], and the utilization of primate models of cerebral amyloid [9] permits preclinical testing of novel diagnostic and therapeutic approaches. 

Cholinesterase inhibitors are a very important class of compounds related to cholinomimetics. Besides their therapeutic importance, a few of them are used as pesticides in agriculture, and the most toxic are used as chemical poisoning agents. Use of these substances is based on changes that take place after inactivation of cholinesterase or pseudocholinesterase (a less specific enzyme), i.e. effects observed as a result of acetylcholine buildup in neuro-effector compounds. Cholinesterase inhibitors are classified both by their chemical structure as well as by the type of their chemical reaction with the enzyme, which determines their temporary action. 

The extensive studies on substrate and inhibitor specificity, on kinetics of hydrolysis, and on the influence of pH variations on the reactions catalyzed by cholinesterases have given very instructive information on the structure of the active surface and the mechanism of enzymatic hydrolysis. The conclusions reached in the various chapters of the present dis-... 

Unlike the systemic direct-acting cholinergic stimulants (e.g., bethanechol), cholinesterase inhibitors display a relative lack of specificity regarding which cholinergic synapses they stimulate. These drugs tend to inhibit the acetylcholinesterase found at... 

A. A. Brimfield, K. W. Hunter, Jr., D. E. Lenz, H. E Benschop, C. VanDijk, and L. P. A. dejong, Structural and stereochemical specificity of mouse monoclonal antibodies to the organophosphorus cholinesterase inhibitor soman, Molec. Pharmacol, 25 32-39 (1985). 

Donepezil was the second cholinesterase inhibitor approved in the US [6]. It is currently the only acetylchohnesterase approved by the FDA for the treatment of severe Alzheimer s disease. Donepezil is a reversible, noncompetitive chohnesterase inhibitor. It has a high binding specificity for brain acetylcholinesterase, with httle to no affinity for butylchohnesterase. Compared with the other cholinesterase inhibitors in this class, donepezil may be better tolerated, with less gastrointestinal side effects. The long half-life of this medication allows once a day dosing (See Table 3). 

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