Acetylcholinesterase drugs

Sussman, J.L., Harel, M., and Silman, I. (1993). Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs. Chemico-Biological Interactions 87, 187-197. 

A systematic search of published literature identified 13 studies concerned with the value for money of acetylcholinesterase inhibitors. The majority were cost analyses of the potential savings in providing health and social care which may accrue from the introduction of these drugs. However, the available clinical evidence is not sufficient to support the assumption that acetylcholinesterase inhibitors are equivalent to other interventions in terms of clinical effect or side effects (Birks and Melzer, 1999 NICE, 2001). Furthermore, research to assess potential cost savings implicitly assumes that... 

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

Anticholinesterase A drug that inhibits the enzyme acetylcholinesterase, which normally inactivates acetylcholine at the synapse. The effect of an anticholinesterase (or cholinesterase inhibitor) is thus to prolong the duration of action of the neurotransmitter. An example is rivastigmine, used in the treatment of Alzheimer s disease. 

Esterases that contribute to human drug metabolism fall into three major classes the cholinesterases (acetylcholinesterase, pseudocholinesterase, butyrylcholinesterase, etc.),... 

HPMA copolymers are water-soluble biocompatible polymers, widely used in anticancer drug delivery (reviewed in Reference [22]). HPMA copolymers containing reactive groups at side-chain termini were previously used for the modification of trypsin [23], chymotrypsin [23,24], and acetylcholinesterase [25]. The modification dramatically increased the acetylcholinesterase survival in the blood stream of mice and the thermostability of modified enzymes when compared to the native proteins. However, the modification involved multipoint attachment of the copolymers to the substrates, which may cause crosslinking. To modify proteins or biomedical surfaces by one point attachment, semitelechelic polymers should be used. 

Once synthesized, acetylcholine is stored in synaptic vesicles until time for its use. Once liberated into the synapse, acetylcholine diffuses across the synaptic cleft in about 100 microseconds (10 " seconds one ten-thousandth of a second), where it interacts with its receptor, and then dissociates from it in the next 1 or 2 milliseconds. Once liberated, acetylcholine is degraded by a second enzyme, acetylcholinesterase, a target for drug discovery (as I develop a bit later). 

The only known change in neurotransmitter metabolism so far detected is a deficiency of acetylcholine in the brain. This has been shown in post-mortem studies on the brains of patients with Alzheimer s disease. Some success in reducing the symptoms of the disease has been obtained with drugs that inhibit the activity of acetylcholinesterase leading to an increase in the acetylcholine concentration, but the improvement is minimal so that its use is controversial. 

H. M. Greenblatt, H. Dvir, 1. Sdman, J. L. Sussman Acetylcholinesterase a multifaceted target for structure-based drug design of anticholinesterase agents for the treatment of Alzheimer s disease. J Mol Neurosci 2003, 20, 369-383. 

To date, three of the four FDA-approved medications used in the treatment of the cognitive aspects of AD are acetylcholinesterase inhibitors, which increase overall levels of acetylcholine (the fourth reduces glutamate excitotoxicity via the NMD A receptor). The identification of compounds that reduce inflammation (and thus immune-mediated neuron loss) or increase the levels of acetylcholine are, therefore, also active areas of drug discovery. 

Another drug with a high incidence of hepatotoxicity is the acetylcholinesterase inhibitor tacrine. Binding of reactive metabolites to liver tissue correlated with the formation of a 7-hydroxy metabolite [13], highly suggestive of a quinone imine metabolite as the reactive species. Such a metabolite would be formed by further oxidation of 7-hydroxy tacrine (Figure 8.11). 

Acetylcholinesterase is a remarkably efficient enzyme turnover has been estimated as over 10 000 molecules per second at a single active site. This also makes it a key target for drug action, and acetylcholinesterase inhibitors are of considerable importance. Some natural and synthetic toxins also function by inhibiting this enzyme (see Box 7.26). 

In this drug class, only sucdnylcholine (succinyldicholine, suxamethonium, AJ is of clinical importance. Structurally, it can be described as a double ACh molecule. Like ACh, succinylcholine acts as agonist at endplate nicotinic cholino-ceptors, yet it produces muscle relaxation. Unlike ACh, it is not hydrolyzed by acetylcholinesterase. However, it is a substrate of nonspecific plasma cholinesterase (serum cholinesterase, p. 100). 

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