Methanesulfonyl fluoride (MSF) has long been known to be a potent

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, 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 th ...

(AChE), the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that regulates

acetylcholine Acetylcholine (ACh) is an organic compound 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 ...

, an important neurotransmitter in both the central and

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...

Technical and physical properties

MSF is a clear, colorless to yellowish

hygroscopic Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption (chemistry), absorption or adsorption from the surrounding Natural environment, environment, which is usually at normal or room temperature. If water mol ...

liquid (attracts and holds water by absorption or adsorption). It is

corrosive Corrosion is a natural process that converts a refined metal into a more chemically stable oxide. It is the gradual deterioration of materials (usually a metal) by chemical or electrochemical reaction with their environment. Corrosion engine ...

and highly toxic. It is an oxydiaphoric inhibitor (acid-transferring inhibitor) of the enzyme

. MSF, which is a liquid at room temperature, has a vapor pressure of 19.2 mmHg, slightly more volatile than water which has a vapor pressure of 18.8 mmHg at 21 °C. This vapor has an LCt₅₀ (lethal concentration, 50% death rate in a given time) in rats of between 4 and 5 parts per million (ppm) during one hour of exposure or between 1 and 1.2 ppm during 7 hours of exposure. MSF produced no subtle biological effects from direct action of MSF independent of its ability to inhibit cholinesterase. Repeated exposures to 1/10 of the LCt₅₀ did not produce overt systemic toxicity or significant pathology. MSF can also cause severe skin burns and serious eye damage, if contact is made. It is a

lachrymator Tear gas, also known as a lachrymatory agent or lachrymator (), sometimes colloquially known as "mace" after the Mace (spray), early commercial self-defense spray, is a chemical weapon that stimulates the nerves of the lacrimal gland in the ey ...

and its vapor causes tears in eyes. Methanesulfonyl fluoride has a pungent odor. It undergoes decomposition on heating to liberate additional toxic fumes of

fluorides Fluoride (). According to this source, is a possible pronunciation in British English. is an inorganic, monatomic anion of fluorine, with the chemical formula (also written ), whose salts are typically white or colorless. Fluoride salts typi ...

and

sulfur oxides Sulfur oxide Sulfur oxides (SOx) are a group of chemical compounds formed by the combination of sulfur and oxygen. The most common SOx are sulfur dioxide (SO2) and sulfur trioxide (SO3). SOx are produced naturally through volcanic activity and are ...

(SO_x).

Synthesis

A typical synthesis is to treat

methanesulfonyl chloride Methanesulfonyl chloride (mesyl chloride) is an organosulfur compound with the formula . Using the organic pseudoelement symbol Ms for the methanesulfonyl (or mesyl) group –, it is frequently abbreviated MsCl in reaction schemes or equations. It ...

with

potassium fluoride Potassium fluoride is the chemical compound with the formula KF. After hydrogen fluoride, KF is the primary source of the fluoride ion for applications in manufacturing and in chemistry. It is an alkali halide salt and occurs naturally as the ...

potassium bifluoride Potassium bifluoride is the inorganic compound with the formula . This colourless salt consists of the potassium cation () and the bifluoride anion (). The salt is used as an etchant for glass. Sodium bifluoride is related and is also of commerci ...

in water and then steam distill the product out.

Therapeutic study

Animal studies have shown that MSF-induced inhibition of AChE is highly selective for the brain when it is studied in vivo. MSF is an irreversible inhibitor of AChE and its inhibition of AChE is only overcome by de novo synthesis of new AChE in each tissue. The recovery of AChE activity in the brain is less than one-tenth as rapid as AChE recovery in the gastrointestinal system, allowing very high accumulated AChE inhibition in the brain with clinically insignificant AChE inhibition in peripheral tissues. The high selectivity of MSF for inhibition in the brain has suggested that it could be used as a treatment for dementia of the Alzheimer type, that it is effective in reducing the persistent cognitive deficit after stroke, and it is highly effective in reducing normal age-related memory impairment, making aged rats perform as well as younger rats. Methanesulfonyl fluoride has been tested successfully in three human clinical trials as a treatment for Alzheimer's dementia. Two Phase I clinical trials testing for safety of MSF in humans at the doses proposed for treating dementia have shown that it is well tolerated and relatively free of the side effects of nausea, vomiting, and diarrhea that are produced by the current cholinesterase inhibitors used for the treatment of Alzheimer's dementia. Furthermore, a Phase II, clinical trial testing both the safety and the efficacy of MSF found that it was well tolerated in the aged patients, and it was highly effective in reducing the symptoms of Alzheimer's dementia. US Patent has been issued for the use of MSF for the treatment of dementia.

References

{{Acetylcholine metabolism and transport modulators Sulfonyl halides Acetylcholinesterase inhibitors