Cholinesterases discovery

A typical example is succinylcholine (suxamethonium, 7.62), although the discovery of this agent predates by decades the concept of soft drugs. In most individuals, this curarimimetic agent is very rapidly hydrolyzed to choline by plasma cholinesterase with a tm value of ca. 4 min [76] [134],... 

Synthetic studies for the discovery of effective antidotes for cholinesterase inhibitors are continuing . Various reactivity studies of oximates with different functional organophosphorus compounds, such as phosphinates, phosphonates, phosphates and thiono analogues (shown in Scheme 5), have been reported . ... 

The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer s disease patients led to the use of drugs that would enhance the actions of acetylcholine in the brain. Therapeutic agents approved for the treatment of Alzheimer s disease are the cholinesterase inhibitors, drugs that block the breakdown of acetylcholine and increase the availability of the neurotransmitter in synapses (see Chapter 12). These drugs are palliative only and do not cure or prevent neurodegeneration. 

One way of improving the therapeutic value of physostigmine in the treatment of AD is the use of slow-release forms. Some of these are currently in clinical development. The search for cholinesterase inhibitors with longer half-lives and stronger effects led to the discovery of the aminoacridines, tacrine and its major metabolite, velnacrine maleate [Davis and Powchik... 

The vital role of the acetylcholine-hydrolyzing enzyme AChE in terminating cholinergic neurotransmission has been recognized for almost as many years as ACh has been recognized as a neurotransmitter (Dale, 1914a, b). For nearly as long, AChE research was intimately linked to the study of its inhibitors [Loewi et al, 1926, cited in Loewi s Nobel lecture (http //nobelprize.org/nobel prizes/medicine/ laureates/1936/loewi-lecture.html) and by Dale, 1962]. The vulnerabihty of cholinesterases to certain natural compounds promoted the discovery and synthesis of new inhibitors for use as pesticides, therapeutics, and, unfortunately, as chemical... 

The pharmacologists and clinical chemists interest in succinylcholine arose from the belief that the hydrolysis, and therefore inactivation, of the drug was brought about by the action of cholinesterase, and that in cases of prolonged response, the patient had a deficiency of the enzyme. The investigation of this thesis led to the discovery of the genetically determined variants of cholinesterase, which are described in Section 2. 

The discovery of an individual having no detectable serum cholinesterase activity was reported by Liddell et al. (L33) in 1962. Such individuals are said to possess a silent gene for cholinesterase, and to date, about 105 subjects have been reported to be homozygous for silent cholinesterase. Simpson and Kalow (S27) presented evidence that the silent cholinesterase gene is allelic to the usual cholinesterase gene. 

Van Ros and Druet (V2) reported the discovery of a slow-migrating cholinesterase variant, which they named Cg, in the sera of four African subjects. Although this may be a hereditary trait, its familial nature has not been demonstrated. These same authors also studied by two-dimensional electrophoresis two other Africans who each had a pair of additional slow bands which were called and C. Again, the possibility that these may be genetic in origin has not been demonstrated. None of these three bands is identical to those which were identified as the fetal band or storage bands by Harris et al. (H6). 

The discovery that organophosphates such as diisopropyl fluoro-phosphate (DFP) inhibit cholinesterase by irreversible phosphorylation of a basic group at the esteratic site led to the use of P P]DFP to ascertain the chemical nature of the DFP-binding site. Jansz et al. (J2) found that the structure of the P peptide of horse serum cholinesterase was Phe-Glu-Ser-Ala-Gly-Ala-Ala-Ser This indicated the serine hydroxyl as the... 

At around the same time, a small circle of Nazi officials learned about the discovery of Soman, one of the most deadly nerve agents known to man, which stiU required further development. Unbeknown to Schrader and many others working in the chemical warfare field, Richard Kuhn, director of the Kaiser Wilhelm Institute for Medical Research in Heidelberg, and his team of scientists had been commissioned by the military to screen various organophosphorus compounds for their level of cholinesterase (ChE) inhibition, and had discovered Soman in the process. When inhaled. Soman turned out to be twice as toxic as Sarin, was able to penetrate through the skin, and quickly affected the central nervous system. Because it inhibited cholinesterase very rapidly, the effective use of antidotes such as atropine was considerably reduced. Experiments on dogs and apes at Gross laboratory in Elberfeld quickly established the enormous toxicity of the new substance. 

The authors are very interested in this enzyme too, in the context of the project INMOLFARM - Molecular Innovation and Drug Discovery (ALENT-57-2011-20), which involves the discovery of new drugs for Alzheimer s and Parkinson s diseases and are currently developing intramolecular catalytic arylations for making libraries of cholinesterase inhibitors. 

In the lead-up to World War II, the Germans forever changed chemical warfare with the discovery of the organophosphorus nerve agents (Goebel, 2008). These agents inhibit cholinesterase enzymes in the nerve synapse responsible for the breakdown of the neurotransmitter acetylcholine (ATSDR, 2008). This results in the accumulation of the neurotransmitter in the synapse and overstimulation of the nervous system. This can result in subsequent respiratory failure and death (ATSDR, 2008). 

Plant-originated anti-ChEs, such as huperzine A, have been used for thousands of years in the treatment of aging-induced memory impairment (Haviv et al., 2007). In 1877, prior to the discovery of ACh as a neurotransmitter in the brain, physostigmine (eserine)— a carbamate extracted from the seeds of Physostigma venenosum—became the first cholinesterase inhibitor used therapeutically to control increased ocular pressure caused by wide-angle glaucoma (Taylor, 1996). 

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