BI514 Pharmacology
Pharmacology: Principles and Drug Targets
Drug Targets
Drug Targets II
Pharmacology of The Peripheral Nervous System
Pharmacology in The Cardiovascular System
Bronchial Asthma
Bronchial Asthma II
Endocrine Pharmacology
Reproductive Pharmacology
Drug Metabolism and Distribution
Statins
Central Nervous System
Pharmacology of the CNS
Anxiety
Pharmacology of The CNS II
General Anaesthesia
General Anaesthesia II
Analgesic Drugs
Antiviral Therapy
Antiviral Drugs
Hepatitis Viruses
Cancer: Anti-Cancer Drugs
,Pharmacology: Principles and Drug Targets
- 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:
Pharmacology: Principles and Drug Targets
Drug Targets
Drug Targets II
Pharmacology of The Peripheral Nervous System
Pharmacology in The Cardiovascular System
Bronchial Asthma
Bronchial Asthma II
Endocrine Pharmacology
Reproductive Pharmacology
Drug Metabolism and Distribution
Statins
Central Nervous System
Pharmacology of the CNS
Anxiety
Pharmacology of The CNS II
General Anaesthesia
General Anaesthesia II
Analgesic Drugs
Antiviral Therapy
Antiviral Drugs
Hepatitis Viruses
Cancer: Anti-Cancer Drugs
,Pharmacology: Principles and Drug Targets
- 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:
