Methanesulfonyl fluoride

MSF is a clear, colorless to yellowish hygroscopic liquid (attracts and holds water by absorption or adsorption). It is corrosive and highly toxic. It is an oxydiaphoric inhibitor (acid-transferring inhibitor) of the enzyme acetylcholinesterase.{{cite journal | pmid = 14033210 | year = 1963 | last1 = Kitz | first1 = R | last2 = Wilson | first2 = IB | title = Acceleration of the rate of reaction of methanesulfonyl fluoride and acetylcholinesterase by substituted ammonium ions | volume = 238 | pages = 745–8 http://www.jbc.org/content/238/2/745.full.pdf#page=1&view=FitH free, automatic full text pdf download, to read offline | journal = The Journal of Biological Chemistry }} 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.{{cite journal | doi = 10.1080/15298667991430596 | title = Three-month inhalation exposure study with methane sulfonylfluoride | year = 1979 | last1 = Hine | first1 = C.H. | last2 = Lyons | first2 = J. | last3 = Eisenlord | first3 = G.H. | last4 = Wright | first4 = J.A. | last5 = Long | first5 = J.E. | journal = American Industrial Hygiene Association Journal | volume = 40 | issue = 11 | pages = 986–92 | pmid = 532785}} MSF can also cause severe skin burns and serious eye damage, if contact is made. It is a lachrymator and its vapor causes tears in eyes.[https://fscimage.fishersci.com/msds/20835.htm MSDS], Fisher Scientific

Methanesulfonyl fluoride has a pungent odor. It undergoes decomposition on heating to liberate additional toxic fumes of fluorides and sulfur oxides (SO_x).{{cite book | title=Extremely Hazardous Substances: Superfund Chemical Profiles | url=https://books.google.com/books?id=gN3fgN0JZroC&pg=PA997 | access-date=25 July 2012 | year=1988 | publisher=William Andrew | isbn=978-0-8155-1166-3 | page=997}}

A typical synthesis is to treat methanesulfonyl chloride with potassium fluoride or potassium bifluoride in water and then steam distill the product out.{{cite journal|first1 = T. | last1 = Gramstad | first2 = R. N. | last2 = Haszeldine|year=1956|title=33. Perfluoroalkyl derivatives of sulphur. Part IV. Perfluoroalkanesulphonic acids|journal=Journal of the Chemical Society (Resumed)|pages=173–180|doi=10.1039/JR9560000173}}

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.{{Cite book | doi = 10.1007/978-1-4613-2179-8_62 | chapter = Sulfonyl Fluorides as Possible Therapeutic Agents in Alzheimer's Disease: Structure/Activity Relationships as CNS Selective Cholinesterase Inhibitors | title = Alzheimer's and Parkinson's Disease | series = Advances in Behavioral Biology | year = 1986 | last1 = Moss | first1 = D. E. | last2 = Rodriguez | first2 = L. A. | last3 = Herndon | first3 = W. C. | last4 = Vincenti | first4 = S. P. | last5 = Camarena | first5 = M. L. | isbn = 978-1-4612-9283-8 | volume = 29 | pages = 551–556 }}{{cite journal | doi = 10.1111/bcp.12018 | title = A Randomized Phase I Study of Methanesulfonyl Fluoride, an Irreversible Cholinesterase Inhibitor, for the Treatment of Alzheimer's Disease | year = 2012 | last1 = Moss | first1 = D.E. | last2 = Fariello | first2 = Ruggero G. | last3 = Sahlmann | first3 = Jörg | last4 = Sumaya | first4 = Isabel | last5 = Pericle | first5 = Federica | last6 = Braglia | first6 = Enrico | journal = British Journal of Clinical Pharmacology | pages = 1231–1239| volume = 75 | issue = 5 | pmid=23116458 | pmc=3635594}} 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,{{cite journal | doi = 10.1016/j.brainres.2005.01.028 | title = Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates simple learning and memory deficits in ischemic rats | year = 2005 | last1 = Borlongan | first1 = Cesario V. | last2 = Sumaya | first2 = Isabel C. | last3 = Moss | first3 = Donald E. | journal = Brain Research | volume = 1038 | pages = 50–8 | pmid = 15748872 | issue = 1| url = https://zenodo.org/record/1258814 | type = Submitted manuscript }} and it is highly effective in reducing normal age-related memory impairment, making aged rats perform as well as younger rats.{{cite journal | doi = 10.1016/0197-4580(93)90127-W | title = Chronic methanesulfonyl fluoride enhances one-trial per day reward learning in aged rats | year = 1993 | last1 = Malin | first1 = David H. | last2 = Plotner | first2 = Robert E. | last3 = Radulescu | first3 = Sarah J. | last4 = Ferebee | first4 = Robert N. | last5 = Lake | first5 = J.Ronald | last6 = Negrete | first6 = Pilar G. | last7 = Schaefer | first7 = Peggy J. | last8 = Crothers | first8 = Marie K. | last9 = Moss | first9 = Donald E. | journal = Neurobiology of Aging | volume = 14 | issue = 4 | pages = 393–5 | pmid = 8367021 }}

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.{{cite journal | pmid = 10192638 | year = 1999 | last1 = Moss | first1 = DE | last2 = Berlanga | first2 = P | last3 = Hagan | first3 = MM | last4 = Sandoval | first4 = H | last5 = Ishida | first5 = C | title = Methanesulfonyl fluoride (MSF): A double-blind, placebo-controlled study of safety and efficacy in the treatment of senile dementia of the Alzheimer type | volume = 13 | issue = 1 | pages = 20–5 | journal = Alzheimer Disease and Associated Disorders | doi=10.1097/00002093-199903000-00003}} 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.{{Cite patent | title = Sulfonyl fluorides for the treatment of Alzheimer's disease | inventor = Moss; Donald Eugene | country = US | number = 5798392 | gdate = 1998-08-25 }}

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{{Acetylcholine metabolism and transport modulators}}

Category:Sulfonyl halides

Category:Acetylcholinesterase inhibitors