Chapter 22

A fine balance of binding interactions is required of a neurotransmitter. What do you think is meant by this and what consequences does it have for drug design?

Neuromuscular blocking activity for tubocurarine is associated with a pharmacophore where the distance between two charged nitrogen atoms is \(1.15 \mathrm{~nm}\). Decamethonium can adopt a folded conformation where the \(\mathrm{N}-\mathrm{N}\) separation is \(1.14 \mathrm{~nm}\). Octamethonium is an analogue of decamethonium which contains an eightcarbon bridge between the charged nitrogens. The fully extended conformation is the most stable conformation and corresponds to a \(\mathrm{N}-\mathrm{N}\) distance of \(1.157 \mathrm{~nm}\). Discuss whether octamethonium is likely to be more active than decamethonium.

An electrostatic gradient has been proposed that guides acetylcholine into the active site of the acetylcholinesterase enzyme. Can you foresee any problems associated with the presence of such a gradient? It has also been proposed that there may be a 'back door' into the active site. What do you think this means, how could it occur, and why would it be necessary?

Research is being carried out to design Alzheimer's drugs that will inhibit both acetylcholinesterase and butyrylcholinesterase, despite the fact that the former enzyme is more effective at catalysing the hydrolysis of acetylcholine. Why do you think this approach is considered relevant? What might be the disadvantages of such an approach?