AChE inhibitors

Question 1

What is an AChE?

Answer 1

• acetylcholinesterase
• enzyme which breaks ACh into choline and acetylCoA

Question 2

What are AChE inhibitors, AChEIs?

Answer 2

• chemicals that prevent AChE from breaking ACh down
• increasing ACh level and action (prolonged availability = more binding)

Question 3

Why are AChEIs used?

Answer 3

Clinical use
- glaucoma (damaged optic nerve in eye)
- Alzheimer’s disease (degradation of neuronal connection
- mathsthenia gravis (muscle weakness)
Other uses
- chemical warfare agents, pesticides

Question 4

How does ACh bind to AChE?

Answer 4

• ionic bond between aa aspartate and cationic centre in ACh
• hydrogen bonding between aa tyrosine and ACh
• aa serine and histidine are key
• serine acts as nucleophile, attacking ester of ACh
• histidine acts as base catalyse

Question 5

What are the classes of AChE inhibitors?

Answer 5

• tetraalkylammonium ions
  8- quaternary ammonium ions
• carbamates [best]
• organophosphates

Question 6

Why can these chemicals bind to AChE?

Answer 6

• tetraalkylammonium ions, quaternary ammonium ions and carbamates have a cationic centre [like in ACh]
• carbamates also have ester group [more similar to ACh]

Question 7

Outline effects and uses of tetraalkylammonium ions

Answer 7

• used for diagnostic purposes
• very short lasting = not efficient
• potency increases with alkyl chain (but then cannot fit active site
• reversible non-covalent inhibitor

Question 8

Outline effects and uses of quaternary ammonium ions

Answer 8

• used for diagnostic purposes [e.g. for myasthenia gravis]
• short acting = not efficient
• reversible non-covalent inhibitor

Question 9

Outline effects and uses of carbamates

Answer 9

• treating glaucoma, atropine poisoning myasthenia gravis, Alzheimer’s disease
• intermediate duration of action
• reversible inhibitors

Question 10

How do carbamates works?

Answer 10

• inactivate AChE active site by transferring carbamoyl group, competing with ACh
• carbamate group is nucleophilically attacked by serine
• carbamoylated enzyme slowly hydrolysed [slower than ACh = inactivating enzyme for longer]

Question 11

Why is the polarity of drugs (e.g. carbamates) important?

Answer 11

• polar drugs cannot pass through blood brain barrier
• carbamates that are polar cannot treat Alzheimer’s
  e.g. physostigmine not polar = used to treat Alzheimer’s

Question 12

Outline effects and uses of organophosphates

Answer 12

• clinically used to treat glaucoma
• but toxic and irreversible (covalent): used as nerve gas
• also used as pesticides, fatal when O present, inactive/excreted when S present

Question 13

What is an antidote for organophosphates?

Answer 13

e.g. drug: pralidoxime
- cleaves P-O bond off serine (freeing active site = regenerating enzyme)
- however it is polar: cannot pass through bbb
- use prodrug: e.g. ProPAM (free base passes bbb)

Question 14

How are AChEIs used in treating Alzheimer’s disease?

Answer 14

• Alzheimer’s - progressive cognitive impairment as neurons are lost = lose functional skills
• result of reduced cholinergic activity
• AChEIs slow breakdown of ACh = increasing ACh availability
• compensating for loss of cholinergic activity
  e.g drug: galantine - treats mild Alzheimer’s
• binds to allosteric site to inhibit AChE