How Drugs Bind to Their Targets

• Synthesis of ACh

  1. Glucose is metabolised into pyruvate
  2. Pyruvate enters the carboxylic acid cycle to create acetyl CoA
  3. Through the enzymatic activity of CAT, acetyl CoA and choline are combined to create acetylcholine
• Acetylcholine is packaged in vesicles and stored at the synaptic terminal
• There is a high acetylcholine concentration in vesicles
• Release of ACh

  1. An action potential reaches the synapse, causing voltage gated Ca2+ channels to open
  2. Influx of Ca2+ causes the membrane of acetylcholine vesicles to merge with the membrane of the pre-synaptic neuron to fuse, resulting in acetylcholine release into the synapse
• The high concentration of acetylcholine released into the synapse means that receptors are rapidly saturated
• nAChR opens cation channels causing rapid depolarisation
• mAChR triggers intracellular processes on both the post and pre-synaptic neurons
• Acetylcholine esterase hydrolyses acetylcholine into acetate and choline
• AChE is often close to nAChR
• Often, there is more AChE than receptors
• Choline from degraded acetylcholine is transported back into the pre-synaptic neuron to be synthesised into more acetylcholine
• Activity of drugs is often understood in terms of molecular structure
• ACh can adopt many shapes and bonding patterns due to having bonds that can rotate
• The preferred conformation (lowest energy) of ACh is when the acetyl group is close to the amine group
• Acetylcholine binds to both mAChR and nAChR due to its multiple conformations
• Through having conformational restriction, muscarine and nicotine are selective for mAChR and nAChR respectively
• Removing an acetyl group from acetylcholine reduces its activity significantly
• Removing a methyl group from acetylcholine reduces its activity largely
• Restricting the conformation of acetylcholine (by making it into muscarine) increases its activity significantly
• Adding extra groups to acetylcholine (by making it into atropine) makes a potent antagonist
• Why is atropine such a potent agonist?

  it has added groups which adds binding energy
• Removing the quarternary amine of acetylcholine will result in no activity
• The length of the molecule chain is important for mAChR
• Maximum of five atoms from N for mAChR
• Substituent groups (e.g. methyl) and their positions affects binding strength with mAChR
• β-methyl fits mAChR well
• α-methyl does not fit mAChR well
• Ionic bond at the deep end of the binding pocket or mAChR between carboxyl group of receptor and quarternary amine of drug
• Hydrogen bonds orientate the molecule in the mAChR
• The open end of the mAChR binding pocket accommodates longer chains
• Van der Waal's forces with antagonist in the mAChR due to an aromatic group
•  Bioisosteric Replacement = Replacement of a binding group in a drug with another group
• Bioisoteric replacement can improve the potency or selectivity of a drug
• Carbachol still binds to mAChR but is not metabolised by cholinesterases, therefore prolonging the activation of the receptor
• Adding a β methyl group carbachol makes it selective for mAChR while also prolonging its activation
• How to make carbachol?

  replace acetyl group with an amine group on acetylcholine