1. Binding sites and interactions
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    • 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
    • Covalent
    • Hydrogen bonding
    • Hydrophobic
    • Van der Waals interactions
  2. Tetrodotoxin
    • 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.
  3. Local anaesthesia
    • 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.
  4. 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.
  5. 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'
  6. 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.
  7. General Anaesthetics: Effects
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    • Interact with LGIC's including GABA and glycine receptors/
  8. GABAA receptors
    • LGIC
    • 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.
  9. Insecticides and their targets
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    • DDT (Dichloro-Diphenyl-Trichloroethane): doesn't break down - accumulates.
Card Set
Binding sites/interactions, animal toxins and anaesthetics