AChEIs (Acetylcholinesterase inhibitors)

Enzyme catalysis

Drug design

designing molecules with stronger binding interactions (than normal substrate) results in enzyme inhibitors which block the active site

Very limited

__ structural variation allowed to achieve ACh analogues due to tight fit in the ACh receptor

Reversible AChEIs

Physostigmine, Neostigmine (Prostigmin), Pyridostigmne (Mestinon), Carbaryl, Edrophonium chloride, __ for the treatment of Alzheimer’s disease

Aryl carbamates

superior to alkyl carbamates as AChEIs (acetylcholinesterase inhibitors) because they have better affinity for AChE and therefore carbamylate AChE more efficiently

Aryl

Carbamate AChEIs

Physostigmine, Neostigmine, Pyridostigmine

Physostigmine

tertiary amines → more lipophilic and can cross the BBB

Neostigmine

quaternary ammonium group = cannot cross BBB

Pyridostigmine

lacks CNS activity

orally effective

Edrophonium

quaternary ammonium-substituted phenol

not a carbamate ester of a phenol → does not carbamylate AChE

used iv for diagnosis of myasthenia gravis (it actsrapidly to increase muscle strength)

Carbaryl (Sevin “dust”)

carbamate-derived AChEI

insecticide for use on houseplants and vegetables as well as for control of fleas and ticks on pets

Irreversible AChEIs (Organophosphorous Compounds)

Sarin, Malathion, Dichlofenthion, Chlorpyrifos, Ecothiophate

Sarin

nerve agent

Insecticidal agents

Malathion, Dichlofenthion, Chlorpyrifos

Aging

cleavage of one or more of the phosphoester bonds while the AChE is phosphorylated

• results in an enzyme-substrate complex that is much less likely to undergo hydrolytic regeneration than the original phosphoester

Atropine and pralidoxime

treat nerve agent exposure