acetylcholinesterase inhibitor

Organophosphates like tetraethyl pyrophosphate (TEPP) and sarin inhibit cholinesterases, enzymes that hydrolyze the neurotransmitter acetylcholine.{{Cite web |title=Тетраэтил пирофосфат - Справочник химика 21 |url=https://chem21.info/info/104173/ |access-date=2025-03-18 |website=chem21.info}}

The active centre of cholinesterases feature two important sites, namely the anionic site and the esteratic site. After the binding of acetylcholine to the anionic site of the cholinesterase, the acetyl group of acetylcholine can bind to the esteratic site. Important amino acid residues in the esteratic site are a glutamate, a histidine, and a serine. These residues mediate the hydrolysis of the acetylcholine.{{cn|date=January 2025}}

File:Hydrolysis of acetylcholine.png

At the esteratic site the acetylcholine is cleaved, which results in a free choline moiety and an acetylated cholinesterase. This acetylated state requires hydrolysis to regenerate itself.{{cite journal | vauthors = Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM | title = Acetylcholinesterase inhibitors: pharmacology and toxicology | journal = Current Neuropharmacology | volume = 11 | issue = 3 | pages = 315–35 | date = May 2013 | pmid = 24179466 | pmc = 3648782 | doi = 10.2174/1570159X11311030006 }}{{cite book |url=https://books.google.com/books?id=fRUlBQAAQBAJ |title=Toxic Phosphorus Esters: Chemistry, Metabolism, and Biological Effects |last=O'Brien |first=Richard D. | name-list-style = vanc |date=2013-10-22 |publisher=Elsevier |isbn=978-1-4832-7093-7 |language=en}}

Inhibitors like TEPP modify the serine residue in the esteratic site of the cholinesterase.

File:Inhibition mechanism.png

This phosphorylation inhibits the binding of the acetyl group of the acetylcholine to the esteratic site of the cholinesterase. Because the acetyl group can't bind the cholinesterase, the acetylcholine can't be cleaved. Therefore, the acetylcholine will remain intact and will accumulate in the synapses. This results in continuous activation of acetylcholine receptors, which leads to the acute symptoms of TEPP poisoning.{{cite book |url=https://books.google.com/books?id=RZTVBQAAQBAJ |title=Principles of Toxicology: Environmental and Industrial Applications |last1=Roberts |first1=Stephen M. |last2=James |first2=Robert C. |last3=Williams |first3=Phillip L. | name-list-style = vanc |date=2014-12-08 |publisher=John Wiley & Sons |isbn=978-1-118-98248-8 |language=en}} The phosphorylation of cholinesterase by TEPP (or any other organophosphate) is irreversible. This makes the inhibition of the cholinesterase permanent.

The cholinesterase gets irreversible phosphorylated according to the following reaction scheme{{Cite journal |last1=Sirin |first1=Gulseher Sarah |last2=Zhang |first2=Yingkai |date=2014-10-02 |title=How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study |journal=The Journal of Physical Chemistry A |volume=118 |issue=39 |pages=9132–9139 |doi=10.1021/jp502712d |issn=1089-5639 |pmc=4183371 |pmid=24786171}}

E + PX <=> E-PX ->[k_3] EP + X

In this reaction scheme the E indicates the cholinesterase, PX the TEPP molecule, E–PX the reversible phosphorylated cholinesterase, k₃ the reaction rate of the second step, EP the phosphorylated cholinesterase and X the leaving group of the TEPP.

The irreversible phosphorylation of the cholinesterase occurs in two steps. In the first step the cholinesterase gets reversibly phosphorylated. This reaction is very fast. Then the second step takes place. The cholinesterase forms a very stable complex with TEPP, in which TEPP is covalently bound to the cholinesterase. This is a slow reaction. But after this step the cholinesterase is irreversibly inhibited.

The time dependent irreversible inhibition of the cholinesterase can be described by the following equation.

: $\backslash ln\; \backslash frac\; E\; \{E\_0\}\; =\; \backslash frac\{k\_3\; t\}\{1\; +\; \backslash frac\{K\_I\}\; I\}$

In this formula, E is the remaining enzyme activity, E₀ is the initial enzyme activity, t is the time interval after mixing of the cholinesterase and the TEPP, K_I is the dissociation constant for cholinesterase-TEPP complex (E–PX) and I is the TEPP concentration.{{cn|date=January 2025}}

The reaction mechanism and the formula above are both also compatible for other organophosphates. The process occurs in the same way{{cn|date=January 2025}}.

Furthermore, certain organophosphates can cause OPIDN, organophosphate-induced delayed polyneuropathy. This is a disease, which is characterized by degeneration of axons in the peripheral and central nervous system. This disease will show a few weeks after contamination with the organophosphate. It is believed that the neuropathy target esterase (NTE) is affected by the organophosphate which induces the disease. However, there are no references found, which indicate that TEPP is one of the organophosphates that can cause OPIDN.{{cite journal | vauthors = Lotti M, Moretto A | title = Organophosphate-induced delayed polyneuropathy | journal = Toxicological Reviews | volume = 24 | issue = 1 | pages = 37–49 | date = 2005-01-01 | pmid = 16042503 | doi = 10.2165/00139709-200524010-00003 | s2cid = 29313644 }}

Acetylcholinesterase inhibitors:

• Occur naturally as venoms and poisons (e.g., onchidal)
• Are used as weapons (nerve agents)
• Are used medicinally:
• To treat myasthenia gravis, where they are used to increase neuromuscular transmission.
• To treat glaucoma
• To treat postural orthostatic tachycardia syndrome
• As an antidote to anticholinergic poisoning
• To reverse the effect of non-depolarising muscle relaxants
• To treat neuropsychiatric symptoms of diseases such as Alzheimer's disease, particularly apathy
• To increase chances of lucid dreaming (by prolonging REM sleep){{cite book |last= Yuschak|first= Thomas | name-list-style = vanc |title= Advanced Lucid Dreaming: The Power of Supplements|year= 2006|publisher= Lulu|isbn= 978-1430305422}}
• To treat Alzheimer's disease, the Lewy body dementias and Parkinson's disease. In these neurodegenerative conditions AChEIs are primarily used to treat the cognitive (memory and learning deficits mostly) symptoms of dementia. These symptoms are attenuated due to the role of acetylcholine in cognition in the CNS. There is some evidence to suggest that AChEIs may attenuate psychotic symptoms (especially visual hallucinations) in Parkinson's disease.{{cite book | isbn = 978-0-47-097948-8 | title = Maudsley Prescribing Guidelines in Psychiatry | edition = 11th | vauthors = Taylor D, Paton C, Shitij K | date = 2012 | publisher = Wiley-Blackwell | location = West Sussex }}
• To treat cognitive impairments in patients with schizophrenia. There is some evidence to suggest efficacy in treating positive, negative and affective symptoms.{{cite journal | vauthors = Singh J, Kour K, Jayaram MB | title = Acetylcholinesterase inhibitors for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD007967 | date = January 2012 | issue = 1 | pmid = 22258978 | doi = 10.1002/14651858.CD007967.pub2 | pmc = 6823258}}
• {{lay source |template=cite web |vauthors=Singh J, Kour K, Jayaram MB |title=Acetylcholinesterase inhibitors versus antipsychotics for schizophrenia either alone or in combination with antipsychotics |type=Abstract |website=Cochrane |url=http://www.cochrane.org/CD007967/SCHIZ_acetylcholinesterase-inhibitors-versus-antipsychotics-for-schizophrenia-either-alone-or-in-combination-with-antipsychotics}}{{cite journal | vauthors = Choi KH, Wykes T, Kurtz MM | title = Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: meta-analytical investigation of efficacy | journal = The British Journal of Psychiatry | volume = 203 | issue = 3 | pages = 172–8 | date = September 2013 | pmid = 23999481 | pmc = 3759029 | doi = 10.1192/bjp.bp.111.107359 }}{{cite journal | vauthors = Ribeiz SR, Bassitt DP, Arrais JA, Avila R, Steffens DC, Bottino CM | title = Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature | journal = CNS Drugs | volume = 24 | issue = 4 | pages = 303–17 | date = April 2010 | pmid = 20297855 | doi = 10.2165/11530260-000000000-00000 | s2cid = 45807136 }}
• As a treatment for autism and to increase the percentage of rapid eye movement sleep in autistic children, in line with the mechanism by which they encourage lucid dreaming.{{cite journal | vauthors = Buckley AW, Sassower K, Rodriguez AJ, Jennison K, Wingert K, Buckley J, Thurm A, Sato S, Swedo S | title = An open label trial of donepezil for enhancement of rapid eye movement sleep in young children with autism spectrum disorders | journal = Journal of Child and Adolescent Psychopharmacology | volume = 21 | issue = 4 | pages = 353–7 | date = August 2011 | pmid = 21851192 | pmc = 3157749 | doi = 10.1089/cap.2010.0121 }}{{cite journal | vauthors = Handen BL, Johnson CR, McAuliffe-Bellin S, Murray PJ, Hardan AY | title = Safety and efficacy of donepezil in children and adolescents with autism: neuropsychological measures | journal = Journal of Child and Adolescent Psychopharmacology | volume = 21 | issue = 1 | pages = 43–50 | date = February 2011 | pmid = 21309696 | pmc = 3037196 | doi = 10.1089/cap.2010.0024 }}
• Are used as {{visible anchor|Insecticides|text=insecticides}}. There are two large classes: organophosphates (e.g., malathion) and carbamates:
• {{visible anchor|Resistance}} is widespread due to various mechanisms, including increased metabolism, gene amplification and target site mutations.{{Cite book |last=Siegried |first=Blair D. |title=Biochemical Sites of Insecticide Action and Resistance |publisher=Springer Berlin |year=2001 |isbn=978-3-540-67625-6 |editor-last=Ishaaya |editor-first=Isaac |location=Heidelberg |pages=269–291 |chapter=Mechanisms of Organophosphate Resistance in Insects |doi=10.1007/978-3-642-59549-3_13 |chapter-url=https://doi.org/10.1007/978-3-642-59549-3_13}}{{cite journal |last1=Chatonnet |first1=Arnaud |last2=Lenfant |first2=Nicolas |last3=Marchot |first3=Pascale |last4=Selkirk |first4=Murray E. |date=2017-04-05 |title=Natural genomic amplification of cholinesterase genes in animals |journal=Journal of Neurochemistry |publisher=International Society for Neurochemistry (Wiley) |volume=142 |pages=73–81 |doi=10.1111/jnc.13990 |issn=0022-3042 |pmid=28382676 |s2cid=34155509 |hdl-access=free |hdl=10044/1/48129|url=https://hal.archives-ouvertes.fr/hal-01608096 }}

The clinical guidelines for medication management in people with dementia recommend trialing an AChE inhibitor for people with early- to mid-stage dementia. These guidelines, known as the Medication Appropriateness Tool for Comorbid Health conditions in Dementia (MATCH-D), suggest that these medicines are at least considered.{{cite journal | vauthors = Page AT, Potter K, Clifford R, McLachlan AJ, Etherton-Beer C | title = Medication appropriateness tool for co-morbid health conditions in dementia: consensus recommendations from a multidisciplinary expert panel | journal = Internal Medicine Journal | volume = 46 | issue = 10 | pages = 1189–1197 | date = October 2016 | pmid = 27527376 | pmc = 5129475 | doi = 10.1111/imj.13215 }}{{Failed verification|date=January 2024}}

Some major effects of cholinesterase inhibitors:

• Actions on the parasympathetic nervous system, (the parasympathetic branch of the autonomic nervous system) may cause bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, and decrease intraocular pressure, increase lower esophageal sphincter (LES) tone
• Cholinergic crisis.
• Actions on the neuromuscular junction may result in prolonged muscle contraction.{{Citation|last1=Singh|first1=Ravneet|title=Cholinesterase Inhibitors|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK544336/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=31335056|access-date=2020-10-12|last2=Sadiq|first2=Nazia M.}}
• The effects of neostigmine on postoperative nausea and vomiting are controversial and there is not a clear linkage in clinical practice, however, there is good evidence to support the reduction in risk when anticholinergic agents are administered.{{cite book | first1 = Paul G | last1 = Barash | first2 = Bruce F | last2 = Cullen | first3 = Robert K | last3 = Stoelting | first4 = Michael K | last4 = Cahalan | first5 = M Christine | last5 = Stock | name-list-style = vanc | title = Clinical Anesthesia | date = 15 April 2013 | edition = 7th | pages = 552–554 | publisher = Lippincott Williams & Wilkins | isbn = 978-1-4511-4419-2 }}

Administration of reversible cholinesterase inhibitors is contraindicated with those that have urinary retention due to urethral obstruction.

Hyperstimulation of nicotinic and muscarinic receptors.

When used in the central nervous system to alleviate neurological symptoms, such as rivastigmine in Alzheimer's disease, all cholinesterase inhibitors require doses to be increased gradually over several weeks, and this is usually referred to as the titration phase. Many other types of drug treatments may require a titration or stepping up phase. This strategy is used to build tolerance to adverse events or to reach a desired clinical effect.{{cite journal | vauthors = Inglis F | title = The tolerability and safety of cholinesterase inhibitors in the treatment of dementia | journal = International Journal of Clinical Practice. Supplement | issue = 127 | pages = 45–63 | date = June 2002 | pmid = 12139367 }} This also prevents accidental overdose and is therefore recommended when initiating treatment with drugs that are extremely potent and/or toxic (drugs with a low therapeutic index).

Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include:

• Some organophosphates not listed under "Irreversible" below
• Carbamates
• Physostigmine
• Neostigmine
• Pyridostigmine
• Ambenonium
• Demecarium
• Rivastigmine
• Phenanthrene derivatives
• Galantamine
• Caffeine – noncompetitive (also an adenosine receptor antagonist){{cite journal | vauthors = Karadsheh N, Kussie P, Linthicum DS | title = Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives | journal = Toxicology Letters | volume = 55 | issue = 3 | pages = 335–42 | date = March 1991 | pmid = 2003276 | doi = 10.1016/0378-4274(91)90015-X }}
• Rosmarinic acid – ester of caffeic acid. Found in plants species of family Lamiaceae.{{cite journal | vauthors = Vladimir-Knežević S, Blažeković B, Kindl M, Vladić J, Lower-Nedza AD, Brantner AH | title = Acetylcholinesterase inhibitory, antioxidant and phytochemical properties of selected medicinal plants of the Lamiaceae family | journal = Molecules | volume = 19 | issue = 1 | pages = 767–82 | date = January 2014 | pmid = 24413832 | pmc = 6271370 | doi = 10.3390/molecules19010767 | doi-access = free }}
• Alpha-pinene – noncompetitive reversible {{cite journal | vauthors = Miyazawa M, Yamafuji C | title = Inhibition of acetylcholinesterase activity by bicyclic monoterpenoids | journal = Journal of Agricultural and Food Chemistry | volume = 53 | issue = 5 | pages = 1765–8 | date = March 2005 | pmid = 15740071 | doi = 10.1021/jf040019b }}{{cite journal | vauthors = Perry NS, Houghton PJ, Theobald A, Jenner P, Perry EK | title = In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes | journal = The Journal of Pharmacy and Pharmacology | volume = 52 | issue = 7 | pages = 895–902 | date = July 2000 | pmid = 10933142 | doi = 10.1211/0022357001774598 | s2cid = 34457692 | doi-access = free }}
• Piperidines
• Donepezil
• Tacrine, also known as tetrahydroaminoacridine (THA)
• Edrophonium
• Huperzine A{{cite web | last = Bauer | first = Brent A. | name-list-style = vanc | title = Huperzine A: Can it treat Alzheimer's? | url = http://www.mayoclinic.com/health/huperzine-a/AN02022 | archive-url = https://web.archive.org/web/20120819063030/http://www.mayoclinic.com/health/huperzine-a/AN02022 | archive-date=2012-08-19 | url-status = live | work = Mayo Clinic }}{{cite journal | vauthors = Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ | title = Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis | journal = Journal of Neural Transmission | volume = 116 | issue = 4 | pages = 457–65 | date = April 2009 | pmid = 19221692 | doi = 10.1007/s00702-009-0189-x | s2cid = 8655284 }}
• Ladostigil
• Ungeremine{{cite journal | vauthors = Rhee IK, Appels N, Hofte B, Karabatak B, Erkelens C, Stark LM, Flippin LA, Verpoorte R | title = Isolation of the acetylcholinesterase inhibitor ungeremine from Nerine bowdenii by preparative HPLC coupled on-line to a flow assay system | journal = Biological & Pharmaceutical Bulletin | volume = 27 | issue = 11 | pages = 1804–9 | date = November 2004 | pmid = 15516727 | doi = 10.1248/bpb.27.1804 | doi-access = free }}
• Lactucopicrin
• Acotiamide
• Hybrid/bitopic ligands{{cite journal | vauthors = Messerer R, Dallanoce C, Matera C, Wehle S, Flammini L, Chirinda B, Bock A, Irmen M, Tränkle C, Barocelli E, Decker M, Sotriffer C, De Amici M, Holzgrabe U | display-authors = 6 | title = Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M1 and M2 | journal = MedChemComm | volume = 8 | issue = 6 | pages = 1346–1359 | date = June 2017 | pmid = 30108847 | pmc = 6072511 | doi = 10.1039/c7md00149e }}

Compounds which function as quasi-irreversible inhibitors of cholinesterase are those most likely to have use as chemical weapons or pesticides.

{{colbegin}}

• Organophosphates
• Echothiophate
• Diisopropyl fluorophosphate
• Cadusafos
• Chlorpyrifos
• Cyclosarin
• Dichlorvos
• Dimethoate
• Metrifonate (irreversible)
• Sarin
• Soman
• Tabun
• VX
• VE
• VG
• VM
• Diazinon
• Malathion
• Parathion
• Carbamates
• Aldicarb
• Bendiocarb
• Bufencarb
• Carbaryl
• Carbendazim
• Carbetamide
• Carbofuran
• Carbosulfan
• Chlorbufam
• Chloropropham
• Ethiofencarb
• Formetanate
• Methiocarb
• Methomyl
• Oxamyl
• Phenmedipham
• Pinmicarb
• Pirimicarb
• Propamocarb
• Propham
• Propoxur
• Atypical inhibitors
• Onchidal
• Coumarins

{{colend}}

• Pesticide poisoning
• Parathion S

{{Reflist|35em}}

• {{MeshName|Acetylcholinesterase+inhibitors}}
• [https://web.archive.org/web/20190301095524/http://www.ebi.ac.uk/pdbe/quips?story=AChE Acetylcholinesterase: A gorge-ous enzyme] QUite Interesting PDB Structure article at [http://www.pdbe.org PDBe]

{{Enzyme inhibition}}

{{Antidementia}}

{{Acetylcholine metabolism and transport modulators}}