Slow-Binding Inhibitors of Cholinesterases Could Lead to New Drugs for Several Diseases

A recent study could lead to new treatments for a number of conditions, such as Alzheimer's disease, myasthenia, and neuroprotection.

A recent study noted that slow-binding inhibitors (SBIs) of cholinesterases (ChEs) highlight the pharmaco-toxicological importance of SBI and how they could produce promising new drugs for several diseases.

To conduct the study, researchers evaluated the synthesis of molecules, enzyme and inhibitory kinetics, crystallography, molecular modeling, pharmacokinetics, and pharmacodynamics.

Acetylcholinesterase (AChE) is an SBI that terminates the action of the neurotransmitter in the central cholinergic system, ganglia and at neuromuscular junctions called acetylcholine. AChE has non-cholinergic functions in cell development and embryogenesis, as well as an involvement in pathogenesis of Alzheimer’s disease.

AChE inhibitors have been used for the palliative treatment of Alzheimer’s, glaucoma, and myasthenia. Major cholinergic syndrome is caused by the irreversible inhibition of AChE by organophosphorus compounds and carbamates.

Butyrylcholinesterase (BChE) acts as an endogenous bioscavenger against several esters used as drugs, pesticides, or banned chemical warfare agents. It is considered to be of toxicological and pharmacological importance. However, BChE has no known physiological function, but has been recently found to hydrolyze ghrelin (hunger hormone).

There are certain potent reversible inhibitors that slowly bind to the active center of both ChEs, determining kinetic complexities.

Researchers used residence time, rebinding, and micro-pharmacodynamics — new concepts in pharmacology – to analyze the data.

The results of the study showed that the SBI of ChEs result from either simple slow interaction, induced-fit, or slow conformational selection. At times, the slow equilibrium was followed by an irreversible chemical step.

Since SBIs have pharmacological advantages over the classical reversible inhibitors, it results in the prolonged efficacy with little negative side effects and could lead to a decrease in the amount of pills an individual consumes.

Currently, SBIs of ChEs, especially methyl-uracil derivatives, show promise in the treatment of Alzheimer’s disease, myasthenia, and neuroprotection.

Additionally, the toxicological importance of SBIs suggest it could play a role in the mechanisms of resistance and protection against toxicity by irreversible agents.

As of now, researchers are conducting experiments in vivo on model animals, isolated cholinergic cell systems, and muscles to gain a better understanding of the toxic and therapeutic effects of SBIs.