- Pharmacology – the study of how chemical agents affect the function of living
systems.
- There are 4 drug targets:
o Receptors, ion channels, enzymes, transporters.
- Drugs can either reinforce the activity of its target in responding to the
endogenous substrate or inhibit it.
- Affinity – the ability of a drug to bind to the drug target.
- Efficacy – the ability of a drug-receptor complex to elicit a biological response.
- Specificity – the ability of a drug to bind to one receptor without affecting another.
- Potency – the biological response in relation to the amount administered.
- Specificity is important to minimise any undesired responses to the drug that
can be severe or fatal, reducing the number of side effects caused.
- An antagonist does not necessarily have an efficacy of 0 or not elicit a biological
response, but rather synthesised to have the lowest response as possible.
- Agonist – produces a response.
- Antagonist – does not produce a response.
Drug Targets
4 subtypes of drug targets:
- Ligand-gated ion channels
- GPCR
- Kinase-linked receptors
o Receptors linked to enzyme kinases, adenylate or guanylate cyclases.
- Nuclear receptors
o Receptors that affect gene transcription.
Ligand-gated ion receptor
- N-terminus is extracellular; C-terminus loops back to extracellular.
- Four or five subunits.
- Fast synaptic neurotransmission.
- E.g.
o Nicotinic ACh receptor, GABAA receptor.
- Transmembrane helices form a central pore.
- These receptors open and close in milliseconds and so are more likely to be
found in excitable tissue that is dependent on fast responses to chemical
stimuli.
- The M2 domain lines the central pore.
G-protein coupled receptors
- Extracellular N-terminus; intracellular C-terminus.
- 7 transmembrane domains.
o 3rd loop is long and intracellular and binds the G-protein.
- Most common drug target.
, - Ligand binding can be in transmembrane domains, N-terminal or extracellular
loops.
- At rest, the G-protein is bound to GDP. When a ligand binds, the G-protein
exchanges GDP for GTP. This occurs in the alpha G-protein.
o The α-GTP complex then dissociates and interacts to the 1st target
protein. When the 1st target is bound, GTP is hydrolysed to GDP and the
α-subunit reassociates with the beta-gamma subunits. Target 1 =
adenylate cyclase, etc.
- It is the beta-gamma subunit that dissociates and binds to the 2nd target protein.
- Antagonists have no intrinsic effect but block endogenous ligands from binding.
Speed of response
- Ion channels > GPCRs > enzyme-linked > transcription activating.
GPCR stimulation
1. Agonist binds to GPCR.
2. The α-subunit /GDP interacts with GPCR.
3. GTP replaces GDP.
4. α-subunit/GTP interacts with target protein 1, activating it. Simultaneously,
the βγ-subunit interacts with target protein 2, activating it.
5. GTP hydrolysis and α-subunit dissociates.
6. GDP re-binds TP α-subunit and reassociates with the βγ-subunit.
Drug Targets II
- Guanylate cyclase is an enzyme receptor, whereas adenylate cyclase and
phospholipase C are G-protein enzymes.
SECOND MESSENGERS PROTEIN KINASES
CGMP PKG
CAMP PKA
PLC (IP3 + DAG) PKC
- G-proteins can be stimulators or inhibitory (Gi/Gs).
- GPCR transduction pathways can result in an amplification of the signalling
cascade.
o This is because more than one adenylate cyclase can be activated and
so the subsequent pathways are stimulated, increasing the IMDs that
eventually causes a response.
Law of mass action
- The rate of a reaction is proportional to the product of the concentration of the
reactants.
Rate of forward reaction:
Rate of reverse reaction:
Dissociation constant:
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