Good and Bad AChE InhibitorsPHM142 Fall 2015

Presented bySanielle ColeIngrid LoweVincent LeVincent Nguyen

PHM142 Fall 2015Instructor: Dr. Jeffrey Henderson

What is AChE? AChE refers to the enzyme

acetylcholinesterase. It is a serine hydrolase and a key enzyme in the CNS.

Location Postsynaptic membrane of cholinergic synapses

Function Terminate the action of acetylcholine (and some

other choline esters) by the process of hydrolysis. Acetylcholine is hydrolysed to acetate and choline.

Overall Action of AChE

Mechanism of AChE The active site of AChE consists of two subsites: the anionic

subsite and esteratic subsite. Anionic: Serves to bind a molecule of ACh to the enzyme Esteratic: Location of hydrolytic reaction (contains the catalytic

triad)

There is also a peripheral anionic site distinct from the choline binding pocket of the active site. It serves to bind ACh and other quarternary ligands acting as

non competitive inhbitors

Structure and Mechanism of AChE

Good AChE Inhibitors Inhibit cholinesterase enzyme

Reversible, competitive or non-competitive

Diagnosis/Treatment of diseases Alzheimer’s Disease (AD)

Most common form of dementia Loss of cholinergic neurons in the brain Decreased ACh

Reversible Inhibitors Piperidines

Donepezil (Aricept)

Carbamates Rivastigmine (Exelon)

Phenanthrene Derivatives Galantamine (Razadyne, Nivalin)

Others

Reversible Inhibitors Donepezil

Selective, reversible Binds to peripheral anionic site

Rivastigmine Less selective, slowly reversible Binds to the esteric site

Galantamine Selective, rapidly reversible Binds to anionic site

Irreversible Inhibitors Ophthalmology

Glaucoma

Organophosphorus Compounds Diisopropyl fluorophosphate Echothiophate

Bad AChE Inhibitors Bind irreversibly to the enzyme

Mostly Organophosphorus compounds which are commonly Insecticides and nerve agent/gases

Esters or thiols of phosphate derivatives

General Structure of OPs

Organophosphorus Compounds

E+PX ⇄ E•PX → EP+X OPs are substrate analogues to ACh

The OPs exert their main toxicological effects through non-reversible phosphorylation of esterases in the nervous system

Organophosphates are relatively toxic to both insects and man.

Most Common Examples Insecticides:

ethyl parathion malathion methyl parathion

Nerve Agents: Used in Chemical Warfare Sarin Gas Tabun, Soman VX - VX is the most toxic and long lasting of

the nerve gases

Treatment of Organophosphate Intoxication

Organophosphates irreversibly inhibit AChE at serine residues Leads to muscarinic, nicotinic or central systems crisis

Non-pharmacological treatment Resuscitation, oxygen supply or decontamination

Pharmacological treatment Symptomatic

Parasympatolytics (ex. Atropine) Anticonvulsives (ex. Diazepam)

Causal Oxime reactivators (ex. pralidoxime, trimedoxime, asoxime, obidoxime)

Detoxification of Carbamate Increase water solubility of carbamate to remove in urine

Carboxylesterases (CESs) Hydrolyze carboxyl esters Carbamates are structurally similar to carboxyl esters

Dependent on the chemical structure

Differs with animals

Detoxification of Organophosphorus

Oxidation and hydrolysis Carboxylesterases

Naturally present CESs in mammals called B-esterases Same process as carbamates except final step

The phosphorylated enzyme cannot be reactivated by water One CES molecule per OP molecule

Phosphotriesterases (PTEs) Bond cleavage of phosphorus and leaving group of OPs The final products are easily eliminated One PTE molecule can degrade multiple OP molecules

Summary AChE: Terminates the action of acetylcholine (and some other choline esters) by the process of

hydrolysis. Acetylcholine is hydrolysed to acetate and choline.

Good AChE Inhibitors Diagnosis/Treatment of diseases Alzheimer’s Disease Mostly reversible

Piperidines; Donepezil (Aricept) Carbamates: Rivastigmine (Exelon) Phenanthrene Derivatives: Galantamine (Razadyne, Nivalin)

Few irreversible Organophosphorus Compounds: Diisopropyl fluorophosphate, echothiophate

Bad AChE Inhibitors Insecticides: Ethyl parathion, malathion, methyl parathion Nerve Agents: Used in Chemical Warfare: Sarin gas, Tabun, Soman, VX – VX

Detoxification Carbamates: Carboxylesterases Organophosphorus compounds: Carboxylesterases, phosphotriesterases (PTEs)

Summary continued. Organophosphates irreversibly inhibit AChE at serine residues

Leads to muscarinic, nicotinic or central systems crisis

Non-pharmacological treatment Resuscitation, oxygen supply or decontamination

Pharmacological treatment Symptomatic

Parasympatolytics (ex. Atropine) Anticonvulsives (ex. Diazepam)

Causal Oxime reactivators (ex. pralidoxime, trimedoxime, asoxime, obidoxime)

References Čolović, M. B., Krstić, D. Z., Lazarević-Pašti, T. D., Bondžić, A. M., & Vasić, V. M. (2013).

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology. Current Neuropharmacology, 11(3), 315–335. http://doi.org/10.2174/1570159X11311030006

Hermona S., Shlomo S. (2001). Acetylcholinesterase — new roles for an old actor. Nature Reviews Neuroscience 2, 294-302 . http://doi.org/10.1038/35067589

Katzung BG. Introduction to autonomic pharmacology. In: Basic and clinical pharmacology, 8th edition. USA: The McGraw Hill Companies, Inc, 2001:75–91.

Elersek, T. and Filipic, M. (2011). Organophosphorous Pesticides- Mechanism of Their Toxicity. Stoytcheva, M (Ed.) Pesticides - The Impacts of Pesticides Exposure (Pages 243-260). Croatia: Intech

Prins, J. M., Chao, C.-K., Jacobson, S. M., Thompson, C. M., & George, K. M. (2014). Oxidative stress resulting from exposure of a human salivary gland cells to paraoxon: an in vitro model for organophosphate oral exposure.Toxicology in Vitro : An International Journal Published in Association with BIBRA, 28(5), 715–721. http://doi.org/10.1016/j.tiv.2014.01.009