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.
References
^Greig NH, Utsuki T, Yu Q, Zhu X, Holloway HW, Perry T, et al. (2001). "A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase". Current Medical Research and Opinion. 17 (3): 159–65.
doi:
10.1185/0300799039117057.
PMID11900310.
S2CID21346884.
^Kamal MA, Al-Jafari AA, Yu QS, Greig NH (February 2006). "Kinetic analysis of the inhibition of human butyrylcholinesterase with cymserine". Biochimica et Biophysica Acta (BBA) - General Subjects. 1760 (2): 200–6.
doi:
10.1016/j.bbagen.2005.10.003.
PMID16309845.
^Kamal MA, Klein P, Yu QS, Tweedie D, Li Y, Holloway HW, Greig NH (September 2006). "Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer therapeutic, bisnorcymserine". Journal of Alzheimer's Disease. 10 (1): 43–51.
doi:
10.3233/jad-2006-10108.
PMID16988481.