ANS 27- Modulators of acetylcholine

What is a nicotinic agonist?

• not used therapeutically - they aren’t very active, so they bind to one subset

• Introducing a methyl group into an ach at the alpha position results in a selective nicotinic agonist

• The way to enhance acetylcholine action is to have an acetylcholine modulator

What are acetylcholine esterase inhibitors - to enhance acetylcholine action?

• therapeutic option - enhanced muscle strength, e.g., myasthenia gravis

• can be used to reverse muscle relaxants

• inhibition of acetylcholinesterase makes the action of ACh more potent

• Normally, Ach is degraded rapidly -acts as a control mechanism

• reversible= therapeutic

• irreversible - poison, e.g., organophosphate insecticides

what does the structure of AChE look like?

• catalytic triad- asp, his,ser

• serine protease

• binding interactions,asp- allows docking interaction ,it is the strongest ,tyr - involved in bonding with ester part of ach

• hydrophobic pockets

• a ts as a suicide inhibition

Mechanism of action of ache

What does a good ache drug inhibitor contain?

should contain:

• a leaving group with equal efficiency of dissociation to the acetyl group in ach

• leaving group should produce a residual group bound to serine, which is less susceptible to hydrolysis

• contain a positive charge motif to fix the molecule into the correct orientation in the active site

carbamates ( ureathanes )- the perfect drug

What are carbamates as reversible inhibitors?

• lead compound- physostigmine found in the natural product physostigma venenosum

• used as an indicator og guilt or innocence trials

• The charged nitrogen mimics the charged nitrogen in acetylcholine, ensuring excellent binding in the receptor

carbamate inhibitors mechanism

Why a carbamate?

• resonance stabilisation

• Carbonyl is less electrophilic

• regeneration by a nucleophile- water is more difficult

What is teh derivative of physostigmine

charged nitrogen for enzyme binding
carbamate for enzyme inactivation
aromatic group for additional enzyme binding interactions

What are irreversible inhibitors?

• not therapeutic

• act as poison

• death occurs through asphyxia as muscle cannot be controlled

example- organo phoshate

Form a covalent bond – irreversible inhibitors
Include:
organophosphate insecticides
nerve agents

mechanism

What are the antidotes of poisoning?

• A range of charged oximes are suitable for antidotes

• Usability depends on how quickly ‘ageing’ occurs with each agent

• Reversibility only possible prior to ‘aging’ which can take place in minutes

summary

• Acetylcholine levels can be modulated by inhibiting acetylcholine esterase

• Inhibition can be:
  reversible and therapeutic
  irreversible and poisonous