Cymserine

Derivatives

A number of cymserine derivatives have been developed with much greater selectivity for butyrylcholinesterase, and both cymserine and several of its analogues have been tested in animals, and found to increase brain acetylcholine levels and produce nootropic effects, as well as reducing levels of amyloid precursor protein and amyloid beta, which are commonly used biomarkers for the development of Alzheimer's disease (potentially indicating the drugs as candidates to be the first medicine capable of stopping, and even reversing, the progression of the disease).

Metabolism

The prospect of cymserine administration in Alzheimer's disease patients is hindered by its toxic metabolites. A portion of administered cymserine is metabolized in the body into eseroline, a potent mu opioid agonist and neurotoxin. As such, derivatives of cymserine which share its effects and mechanism of action but differ in their metabolic pathways would theoretically produce much fewer side-effects and have a greatly reduced risk of neurotoxic damage occurring with long-term administration (which could ultimately result in a greater loss of mental capacity than Alzheimer's disease itself). The search for cymserine derivatives which do not serve as prodrugs to eseroline is ongoing.

References

References

1. (2001). "A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase". Current Medical Research and Opinion.
2. (November 2005). "Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent". Proceedings of the National Academy of Sciences of the United States of America.
3. (February 2006). "Kinetic analysis of the inhibition of human butyrylcholinesterase with cymserine". Biochimica et Biophysica Acta (BBA) - General Subjects.
4. (September 2006). "Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer therapeutic, bisnorcymserine". Journal of Alzheimer's Disease.
5. (May 2008). "Kinetics of human serum butyrylcholinesterase inhibition by a novel experimental Alzheimer therapeutic, dihydrobenzodioxepine cymserine". Neurochemical Research.
6. (June 2008). "Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis". Journal of Neural Transmission.
7. (October 1990). "Eseroline, a metabolite of physostigmine, induces neuronal cell death". Toxicology and Applied Pharmacology.