Cymserine Explained

Cymserine is a drug related to physostigmine, which acts as a reversible cholinesterase inhibitor, with moderate selectivity (15×) for the plasma cholinesterase enzyme butyrylcholinesterase, and relatively weaker inhibition of the better-known acetylcholinesterase enzyme. This gives it a much more specific profile of effects that may be useful for treating Alzheimer's disease without producing side effects such as tremors, lacrimation, and salivation that are seen with the older nonselective cholinesterase inhibitors currently used for this application, such as donepezil. 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).^{[1] [2] [3] [4] [5] [6]}

Unfortunately, the extremely promising results of cymserine administration in Alzheimer's 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.^[7] 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 itself). The search for cymserine derivatives which do not serve as prodrugs to eseroline is ongoing.

Notes and References

1. Greig NH, Utsuki T, Yu Q, Zhu X, Holloway HW, Perry T, Lee B, Ingram DK, Lahiri DK . 6 . A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase . Current Medical Research and Opinion . 17 . 3 . 159–65 . 11900310 . 10.1185/0300799039117057 . 2001 . 21346884 .
2. Greig NH, Utsuki T, Ingram DK, Wang Y, Pepeu G, Scali C, Yu QS, Mamczarz J, Holloway HW, Giordano T, Chen D, Furukawa K, Sambamurti K, Brossi A, Lahiri DK . 6 . 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 . 102 . 47 . 17213–8 . November 2005 . 16275899 . 10.1073/pnas.0508575102 . free . 1288010 . 2005PNAS..10217213G .
3. Kamal MA, Al-Jafari AA, Yu QS, Greig NH . Kinetic analysis of the inhibition of human butyrylcholinesterase with cymserine . Biochimica et Biophysica Acta (BBA) - General Subjects . 1760 . 2 . 200–6 . February 2006 . 16309845 . 10.1016/j.bbagen.2005.10.003 .
4. Kamal MA, Klein P, Yu QS, Tweedie D, Li Y, Holloway HW, Greig NH . Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer therapeutic, bisnorcymserine . Journal of Alzheimer's Disease . 10 . 1 . 43–51 . September 2006 . 16988481 . 10.3233/jad-2006-10108 .
5. Kamal MA, Klein P, Luo W, Li Y, Holloway HW, Tweedie D, Greig NH . Kinetics of human serum butyrylcholinesterase inhibition by a novel experimental Alzheimer therapeutic, dihydrobenzodioxepine cymserine . Neurochemical Research . 33 . 5 . 745–53 . May 2008 . 17985237 . 10.1007/s11064-007-9490-y . 5201206 .
6. Kamal MA, Qu X, Yu QS, Tweedie D, Holloway HW, Li Y, Tan Y, Greig NH . 6 . Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis . Journal of Neural Transmission . 115 . 6 . 889–98 . June 2008 . 18235987 . 10.1007/s00702-008-0022-y . 5193500 .
7. Somani SM, Kutty RK, Krishna G . Eseroline, a metabolite of physostigmine, induces neuronal cell death . Toxicology and Applied Pharmacology . 106 . 1 . 28–37 . October 1990 . 2251681 . 10.1016/0041-008X(90)90102-Z .