AChE Inhibitors

  • Created by: LBCW0502
  • Created on: 10-10-18 15:01
Outline the cholinergic system
Depolarisation of presynaptic nerve terminal, Ca enters, ACh released via exocytosis, diffusion across synaptic cleft, binds to NAChR, Na enters postynaptic neuron. AChE breaks down ACh, acetate and choline, returns to presynaptic terminal
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Describe features of AChE
AChE, BChE. Efficient enzyme. Rate of catalysed reaction approaches diffusion controlled limit. Turnover number 25000/s. 1 molecule of substrate converted to products in 40 microseconds. ACh cleared before arrival of next impulse
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Describe the active site of AChE
Composed of two substrates. Esteratic subsite contains triad residues (Ser, His, Glu). Anionic subsite (Trp, Phe) accomodates charged quaternary ammonium of choline moiety
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Describe features of the AChE binding site (1)
Hydrophobic pockets involve methyl groups. Anionic binding region contains aspartate for ionic bonding. Ester binding region involves His and Ser. H bonding with tyrosine to keep substrate intact
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Describe features of the AChE binding site (2)
Anionic binding region similar to cholinergic receptor site. Binding and induced fit strains ACh and weakens bonds. Molecule positioned for reaction with His and Ser
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Outline ACh hydrolysis mechanism
Ser OH carries out nucleophilic attack on ester bond. His N accepts proton. Formation of good leaving group (weak base, ROH). Water used for hydrolysis. His N donates proton. Formation of acetate to be released
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Describe features of AChE mechanism of catalysis
Serine and water are poor nucleophiles. Histidine acts as basic catalyst. Choline and serine are poor leaving groups. Histidine acts as an acid catalyst to help leaving group. Very efficient. Fast hydrolysis. Aspartate involved
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Describe features of MOA of AChE inhibitors
No inhibito - rapid hydrolysis, active site free for ACh. Inhibitor present (carbamates) - slow hydrolysis, active site occupied for longer, unavailable for endogenous ACh
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Describe the rate of hydrolysis and extent of inhibition
Acetylcholine - fast hydrolysis, low inhibition. Neostigmine - slow hydrolysis, high reversible inhibition. Di-isofluorophosphate (organophosphates) - very slow hydrolysis, high irreversible inhibition
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Describe features of AChE inhibitors
Prevents ChEs from breaking down ACh which consequently increases the level and duration of action of ACh. ChEIs such as organophosphates and carbamates serve as insecticides, pesticides, warfare agents and drugs
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AChE inhibitors are used for which treatments?
Used in treatments for glaucoma, myasthenia gravis and Alzheimer's disease
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Describe features of the chemical class of AChE inhibitors
Tetraalkylammonium ions (non-covalent reversible, binds to anionic site), quaternary ammonium alcohol (short acting, non-covalent irreversible diagnosis of myasthenia gravis), carbamates, organophosphates
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Describe features of carbamates
Carbamyl esters inactivates enzyme by transferring carbamyl group. Competes with ACh. Donate carbamyl group to enzyme blocking active site. Carbamylated enzyme reactivated by slow hydrolysis, increases ACh activity duration in synapse. 0.5-2 hrs
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Describe the structure of carbamates
Aromatic ring, pyrrolidine N - ionised at blood pH and equivalent to quaternary nitrogen of ACh
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Outline the mechanism of carbamates as a MOA
Ser OH breaks ester bond, His accepts proton, formation of good leaving group (weak base, ArOH), very slow hydrolysis process
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Describe features of Physostigmine (carbamates)
Tertiary amine, acts at postganglionic parasympathetic synapse, medium duration of action. Used to treat glaucoma, atropine poisoning, myasthenia gravis, Alzheimer's disease, acts on NMJ
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Describe features of organophosphates
Agents developed in the Second World War, long acting irreversible inhibitors of AChE, covalent attachment with AChE, treats glaucoma
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Describe the mechanism for organophosphates as a MOA
Ser OH attacks P-F bond, stable bond formed between P and O (irreversible)
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Describe features of organophosphates as insecticides
S=P in mammals - metabolism leads to inactive form. S=P in insects becomes O=P (insect oxidative desulphurisation) which is active, phosphorylation of enzyme leads to death
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Describe features of designing organophosphate antidotes
Need strong nucleophile to cleave P-O bond e.g. hydroxylamine (too toxic for clinical use), increase selectivity by increasing binding interactions with active site. Quaternary N added to bind to anionic region, side chain NOH. Pralidoxime effective
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Why can't Pralidoxime act in CNS?
Cannot cross BBB due to being charged and hydrophilic
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Describe the mechanism for organophosphate antidotes
Active site blocked. Antidote molecule binds to P on organophosphate molecule. Active site becomes free (serine is free)
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Describe features of ProPAM
Prodrug for pralidoxime, passess through BBB as free base, oxidised in CNS to pralidoxime
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Describe the regeneration of AChE by Pralidoxime
Presence of organophosphate leads to decrease in plasma ChE activity. Presence of Pralidoxime leads to increase of plasma ChE activity - regeneration of AChE (see graph)
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Give examples of clinically used AChE inhibitors
Physostigmine, Tacrine, Donepezil, Galantamine, Neostigime, Pyridostigmine, Edrophonium, Rivastigmine
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Describe features of Glaucoma
Inhibition of AChE, stimulation of ciliary body. Increases drainage of fluid/relieves intra-ocular pressure. AChEIs (Ecothiophate/physotigmine). Systemic side effects - sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory issues
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Describe features of Myasthenia Gravis
Auto-immune depletion of ACh receptors. Weakness of face, tongue, double vision, drooping eyelids, difficulty chewing/swallowing/talking. Inhibition of AChE increases ACh at NMJ, more stimulation of muscle (Neostigmine, Pyridostigmine)
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Describe features of Alzheimer's Disease
Age-related neurodegenerative disorder affective cognitive features, loss of neurons in cerebral cortex, reduced ACh activity, use AChE to increase ACh to compensate loss of cholinergic neurons
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Describe features of the treatment of Alzheimer's Disease
AChEIs, physotigmine and tacrine, donepezil, rivastigmine, galatamine
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Describe features of Galantamine
Used to treat mild to moderate form of Alzheimer's disease, competitive reversible AChE inhibitor, allosteric ligand at nicotinic AChR. Low concentration - nicotinic APL, higher concentration - nicotinic inhibitor, up-regulate nAChR expression
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What is an alkaloid?
Nitrogenous organic compounds from plants which have physiological actions on humans
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Card 2

Front

Describe features of AChE

Back

AChE, BChE. Efficient enzyme. Rate of catalysed reaction approaches diffusion controlled limit. Turnover number 25000/s. 1 molecule of substrate converted to products in 40 microseconds. ACh cleared before arrival of next impulse

Card 3

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Describe the active site of AChE

Back

Preview of the front of card 3

Card 4

Front

Describe features of the AChE binding site (1)

Back

Preview of the front of card 4

Card 5

Front

Describe features of the AChE binding site (2)

Back

Preview of the front of card 5
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