Lecture 3 Flashcards
What are agonists?
Receptor activators
What are antagonists?
Receptor blockers
What is a receptor?
A protein which binds to neurotransmitters, hormones etc and produces a cellular response
Name the two types of receptors
- ionotropic - metabotropic
What is another name for iontropic receptors?
Ligand gated ion channels
What is another name for metabotropic receptors?
G-protein coupled receptors
Mechanisms of agonists
Binding to receptor -> AR complex -> conformational change of receptor= response
How do we measure responses to a drug?
- muscle contraction- second messenger production e.g. cAMP, IP3 - inhibition of transmitter release - change in HR, BP etc
What shape is the agonist log concentration-response curve?
Sigmoidal
What is EC50?
Effective concentration giving 50% of maximal response
Why is there a maximum response?
- finite number of receptors which are all occupied- response is proportional to the AR complex - property of tissue/cell e.g. maximal muscle contraction
What is affinity?
How well a drug binds to a receptor
What is efficacy?
A measure of the response once the drug is bound to a receptor
What is potency?
A combination of affinity and efficacy
Do drugs with the same EC50 always have the same efficacy?
No- drugs can have the same affinity but one drug can have higher efficacy than the other
What is Kd?
Concentration of drug required to occupy 50% of the receptors
What does a low Kd mean?
high binding affinity
Why can you not measure a response of ligand affinity?
Because you can have high affinity but low efficacy and vice versa- you have to look at binding
Mechanism of a ligand binding assay?
Displacement of radio-labelled ligand (3H, 14C, 125I) by a cool ligand
What is an issue of using a ligand binding assay?
Must account for non-specific binding e.g. to plasma proteins
How do we deal with non-specific binding in ligand binding assays?
Increase amount of cold ligand to displace radio-labelled ligand, ensuring that only NSB only occurs with radio-labelled ligand
Why do we see receptor desensitisation?
- loss of receptors (internalisation) - exhaustion of mediators e.g. cAMP - physiological adaption (homeostatic response)
What is tachyphylaxis?
rapidly diminishing response to successive doses of a drug, rendering it less effective
What is the difference between desensitisation and tachyphylaxis?
Tachyphylaxis is a possible mechanism underlying desensitsation
Examples of agonists used clinically
Adrenaline, salbutamol. dopamine, morphine
What is a partial agonist?
- cannot produce a full response (low efficacy) - prevents full agonists - reduces overactivity without reducing basal activity
Why do we use buprenorphine (temgesic) as a partial agonist?
- less abuse liability - less dysphoria
What are inverse agonists?
Agonists that produce the opposite response of a full agonist
Why do we use inverse agonists?
To reduce the constitutive activity (activity without a ligand) of GPCRs
What would an inverse agonist do at the GABA-A receptor?
Decreases the activity of GABA
What is a PAM?
Postive allosteric modulator
What do PAMs do?
Increases coupling to a G protein which makes the agonist more effective
What is a NAM?
Negative allosteric modulator
What do NAMs do?
Reduce effectiveness of the G protein
What is an AGO-PAM?
An agonist with positive allosteric modulatory activity
Why would you use a PAM/NAM?
If you want to increase/reduce activity but don’t want to change the regular temporal pattern, modulate the activity of agonists
What is a competitive antagonist?
- reduces EC50 of an agonist - parallel shift in concentration-response curve - can still achieve a maximum response with increased agonists
What is pA2?
A measurement of antagonist potency
Define pA2
Negative log of the molar concentration of antagonist that reduces the effect of a known agonist concentration by half
What does a larger pA2 value mean?
The better an antagonist is
Why do we have to consider receptor selectivity for antagonists with high pA2 values?
- higher pA2= less selective an antagonist is - risk of antagonising receptors which were not intended
Examples of competitive receptor antagonists
- naloxone - chlorpromazine - beta blockers - atropine - tubocurarine
What is a non-competitive antagonist?
- cannot be outcompeted - bind to allosteric site/covalently bound to binding site - no parallel shift or maximum response
What is the importance of spare receptors?
- allows max response without occupying all receptor (increased sensitivity) - maybe prevent exaggerated responses
How do spare receptors affect Kd and EC50?
Kd ≠ EC50
Examples of non-competitive antagonists
- ketamine (NMDA) - perampanel (AMPA) - 𝛼-bugarotoxin (nicotinic)
What is drug use-dependence (activity/frequency dependence)?
The more receptors a drug preferentially blocks, the more effective it is (basal activity is preserved)
Examples of drugs with use dependence
- epilepsy voltage gated Na+ channels (only block during overactive moments) - cardiac arrythmias Na+ channels (block over active rhythms)
