Binding sites and interactions
- Agonist: Binds to binding site = Activates receptor
- Competitive inhibitor: Binds to binding site = Inhibits receptor activity
- Allosteric activator: Binds somewhere else on receptor = Activates receptor
- Allosteric inhibitor: Binds somewhere else on receptor = Inhibits receptor activity
- Interactions: Drugs match shape of their receptor binding site and form energetically-favourable binding interactions
- Electrostatic interaction … an ionic bond or ‘salt bridge’
- Hydrogen bonding
- Van der Waals interactions
- Potent neurotoxin
- MoA: blocks Na+ channels by physically blocking the pore. Forms Hydrogen bonds with different amino acids in the selectivity filter.
- The postively-charged ‘guanidinium’ group of TTX forms a salt bridge with the domain I aspartate.
- Extensive network of binding interactions make the binding irreversible.
- Works on the peripheral afferent nerves in a restricted area.
- Structure: 1) Tertiary amine group (Nitrogen) with 3 bonds. Can accept a proton and become positively charged.
- 2) Linker - esther or amide (e.g lidocaine) - intense and longer lasting anaesthesia.
- 3) Aromatic ring contributes to hydrophobicity of LA molecule
- MoA: block Na+ channels, preventing action potentials from propagating so pain signals never reach the CNS.
Charged and Uncharged Local Anaesthetics
- LA's can accept a proton (H) on their amine group to become positively charged
- Lidocaine: Uncharged (neutral) when pH >7.9. Charged when pH <7.9
- Uncharged LA's are hydrophobic = can insert into and cross lipid bilayers, including the myelin sheath.
- Myelin sheath 'soaks up' LA's near the point of entry - contributes to their localisation.
- LA's are then concentrated around the axon (nodes of ranvier) where Na+ channels are.
MoA for LA's: The Guarded Receptor hypothesis
- Binding site for LA's is within the pore of the Na+ channel - positively charged LA's have a high affinity for the binding site
- BUT LA's cannot activate the channel so must wait for the channel to open.
- ALSO LA's can only access the channel from the intracellular space
- Solution: LA's must lose their charge in order to cross the cell membrane before regaining their charge and entering the channel from the bottom when it's open.
- Termed 'use-dependent block'
MoA for LA's: Tonic Block
- Channel block has been seen in conditions where nerves are held at hyperpolarisation state.
- Fenestrations: holes in the channel linking the inner pore to the lipid bilayer
- Fenestrations could offer another route of access for LA's
- Benzocaine is permanently uncharged (can't enter through gate) so tonic block would explain their LA effect.
General Anaesthetics: Effects
- Interact with LGIC's including GABA and glycine receptors/
- Activation: binding of the neurotransmitter gamma-Aminobutyric acid (GABA) to the extracellular domain
- Conduction: negatively charged Chloride ions (Cl-).
- Major inhibitory neurotransmitter receptors in the CNS - suppress activity of the CNS
- MoA: Reduce the probability of an action potential firing in the post-synaptic neuron. Termed an ‘Inhibitory Postsynaptic Potential (IPSP)’
- GA's 'potentiate' GABA receptors, increasing their affinity for the GABA ligand which increases the likelihood of the channel opening and conducting more Cl- ions.
Insecticides and their targets
- DDT (Dichloro-Diphenyl-Trichloroethane): doesn't break down - accumulates.