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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.
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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