Acetylcholinesterase Inhibitors

name the two types of enzymes that hydrolyse ACh

AChE and BChE (Butyrylcholinesterase)

ACh is inactivated to give what 2 molecules?

acetic acid and choline

how does the structure of AChE allow the hydrolysis of ACh?

• 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

in ACh mechanism, what is the role of Ser?

nucleophile- attacks C=O on ACh so it is available to act on substrate

in ACh mechanism, what is the role of His?

acts as both acid and base catalyst (H donor/acceptor)

what 3 amino acids is targeted in cholinergic system?

Ser, His, Asp

Serine and water are _________ nucleophiles. What must be added to drive reaction?

poor- catalyst (basic)

Leaving groups are aided by which amino acid residue at cholinergic receptors ?

His- acts as acid catalyst

Why do organophosphates inhibit acetylcholinesterase for so long?

- binding covalently to a serine residue in the enzyme active site

- P-O bond is very stable

what class of AChE are the most important?

Carbamates

what group on carbamates blocks the activity of AChE?

carbamoyl group- undergoes slow hydrolysis- stops AChE acting on ACh

Neostigmine and Pyridostigmine are used in?

local anaesthetics

describe the action of DFP and Echothiophate

Long acting irreversible inhibitors of AChE

organophosphates lead to ?

permanent inhibition of AChE

organophosphates antidotes require what ideal properties (2)?

- Strong nucleophile required to cleave strong P-O bond i.e. Hydroxylamine

- Non-polar

what is Glaucoma?

increased pressure in the eye

how does AChEs treat glaucoma?

-Inhibition of AChE leads to enhanced effect of ACh in stimulation of ciliary body

-increases drainage of fluid from eye

relieves intra-ocular pressure

what is Myasthenia Gravis?

Auto-immune depletion of Acetylcholine (Ach) receptors- leads to flaccid muscles (weakness of face, tongue. double vision or drooping eyelids, difficulty chewing, swallowing and talking)

Alzheimer's disease is characterised by?

loss of neurons in cerebral cortex- reduced cholinergic activity

how to AChE inhibitors treat AD?

-used to prevent breakdown of ACh

-Increased ACh to compensate for loss of cholinergic neurones

-improves cognition (symptomatic relief)