Cymserine is a drug related to

physostigmine Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean a ...

, which acts as a reversible

cholinesterase inhibitor Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. This increases the amount of the acetylcholine or butyrylcholine in the syn ...

, with moderate selectivity (15×) for the plasma cholinesterase enzyme

butyrylcholinesterase Butyrylcholinesterase ( HGNC symbol BCHE; EC 3.1.1.8), also known as BChE, BuChE, BuChase, pseudocholinesterase, or plasma (cholin)esterase, is a nonspecific cholinesterase enzyme that hydrolyses many different choline-based esters. In humans, ...

, and relatively weaker inhibition of the better-known

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme that catalyzes the breakdown of acety ...

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

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...

lacrimation Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...

, and

salivation Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can b ...

that are seen with the older nonselective cholinesterase inhibitors currently used for this application, such as

donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to ...

. 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 Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

levels and produce

nootropic Nootropics ( , or ) ( colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic supplements or drugs and other substances that are claimed to improve cognitive function or to promote re ...

effects, as well as reducing levels of

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator ...

and

amyloid beta Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which i ...

, 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). 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 Eseroline is a drug which acts as an opioid agonist. It is a metabolite of the acetylcholinesterase inhibitor physostigmine but unlike physostigmine, the acetylcholinesterase inhibition produced by eseroline is weak and easily reversible, and ...

, a potent mu opioid agonist and

neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and matur ...

. 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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dr ...

to eseroline is ongoing.

References

{{Acetylcholine metabolism and transport modulators Acetylcholinesterase inhibitors Carbamates Tryptamine alkaloids Pyrroloindoles Isopropyl compounds Phenol esters