Agonists To Antagonists Flashcards
What type of receptors are dopamine receptors?
GPCRs
GPCRs stands for G-Protein Coupled Receptors.
What condition is associated with lost dopamine receptor function?
Parkinson’s Disease
What effect would an agonist have in Parkinson’s Disease?
Improve function
In schizophrenia, dopamine receptors are __________.
Overactive
What effect would an antagonist have in schizophrenia?
Improve function
What happens at very high doses of an agonist in Parkinson’s Disease?
Schizophrenia-like symptoms
What happens at very high doses of an antagonist in schizophrenia?
PD-like symptoms
What do agonists do?
Activate receptors
What are the two conformations of a receptor?
Resting = usually predominates
Active = this state is less stable
What assay is used to measure cAMP levels in β1 adrenoceptor cell lines?
cAMP assay
Known as concentration-effect or concentration-response curve
Has a rectangular hyperbola shape
Drug concentration on the X axis and cAMP concentration on the Y axis
What does Emax represent?
Maximal effect
What does EC50 measure?
Potency —> concentration or dose of drug required to produce a specific effect
Effect is 50% of maximum effect
EC50 is defined as the concentration of agonist giving __________ of Emax.
50%
What is pEC50?
-log EC50
What is the relationship between Emax and Bmax?
Emax is directly related to Bmax
What factors influence the values of EC50 and Emax?
- Ratio of receptors to G-protein
- Number of G proteins receptor activates
- Ratio of G protein to target enzyme
- Stability of product (cAMP broken down by PDE)
- Events downstream of cAMP
As EC50 goes down, what happens to potency?
Potency goes up
What is efficacy in pharmacology?
How well a drug activates a receptor once bound
What is the difference between a full agonist and a partial agonist?
- Full agonist: 100% efficacy
- Partial agonist: <100% efficacy where lower percentage is weak
What is the functional Gaddum equation used for?
Predicting surmountable antagonism
What characterizes a competitive antagonist?
- No change in maximum response
- Increase in apparent EC50 for the agonist
- Parallel shift of the curve to the right
What is a non-competitive antagonist?
Binds to a different site than the agonist
What is an example of an irreversible competitive antagonist?
Clopidogrel = covalent modification of the receptor
Cobra toxin = ultra slow dissociation
What is the significance of dose in pharmacology?
It is crucial for determining effects in whole organism assays
What does ED50 measure?
Potency in dose-effect relationships
Potency increases as ED50 __________.
Decreases
Effects of agonists on a receptor
Causes the equilibrium to favour the active state as the binding energy stabilises it
What are the different types of assays?
- Cell based biochemical assay —> uses wells, often used for GPCRs and receptor activation is measured by measuring concentrations of intracellular messengers
- Isolated organ assay —> measures how normal physiological functions of the organ changes in response to drugs
- Cell based electrophysiological assay —> measures how membrane potential changes in response to drugs & requires electrodes on or in the cell = measures ion channel activity
- Whole animal assay or human trials —> measures changes a drug produces on physiology, behaviour or disease, tends to be expensive
How to find Emax and EC50
Emax is where the curve plateaus and EC50 is half of Emax followed down to the X axis
Log concentration-effect curves
S-shaped (sigmoid) shape
Log EC50 = half of Emax also is log [drug]
What is the relationship between EC50 and KD?
EC50 is directly related to KD
What happens in the case of ‘spare’ receptors?
When one receptor activates multiple signalling cascades or only a few are activated instead of all
Emax is reached before Bmax and EC50 will be less than KD
So they are not directly related
How does EC50 behave like KD?
As EC50 goes down, potency goes up
How does a partial agonist differ in efficacy compared to a full one?
Has the same logE50 value but will only have partial efficacy = same potency but different efficacy
What is the efficacy of antagonists?
Zero as they occupy the binding site but do nothing
Important features of competitive antagonism
- the maximal effect of the agonist is not changed
- in the presence of an antagonist, need to use more agonist to bring about a particular effect
- increase in the apparent EC50 for the agonist
- parallel shift in the curve to the right
What is apparent EC50?
EC50 X [I]/Ki
To get EC50, it is 1 + [I]/Ki
Types of antagonism
- Reversible competitive antagonism/reversible orthosteric antagonism —> same site as the agonist & surmountable (able to overcome by increasing concentration of agonist)
- Non-competitive antagonism —> different site to the agonist, can get simultaneous binding & antagonist changes conformation of the receptor so agonist can’t activate it
Non-competitive antagonism
Also known as negative allosteric modulator
Reduces maximum effect an agonist can produce
Insurmountable (can’t overcome by increasing concentration of agonist)
Irreversible competitive antagonism
Insurmountable
Antagonist is permanently eliminating receptors from the pool an agonist can bind to = reduces maximum response the agonist can achieve
Behave like a non-competitive antagonist
Antagonists and tone
Vagal tone keeps the heart beating at a lower rate
An antagonist such as Atropine blocks receptors so that ACh can’t bind and so heart rate increases
Even though the antagonist is ‘doing nothing’ directly, it is still producing an effect by blocking the receptors and thus ACh access
What do whole organism assays measure?
Absorption (some drugs are metabolised in the GI tract)
Distribution (how the drug moves to the site of action)
Metabolism (drugs are metabolised in the liver)
Excretion (excreted in the urine via the kidney)
Analysing dose-effect data
- Log X axis
- Maximal effect can be continuous (e.g. blood pressure) or can be all or nothing (cured/not cured)
- Potency is measured by ED50 not EC50 but behaves in the same way
- Can use pED50 = -logED50
