Drug Receptor Interactions Flashcards
Explain the importance of understanding receptors
- Many drugs work by targeting receptors
- Transmitters and hormones act through binding to receptors
- Chemical toxicity - many toxic mechanisms that arise as a result of exposure to certain chemicals are receptor-mediated
- Viral toxicity - pathogens can target receptors
Outline the structure of ionotropic receptors (i.e ion channel receptors)
- Can be voltage/ligand-gated
- Form aqueous pathways through which ions can pass through upon the binding of a ligand to receptors/sudden changes in membrane potential
- Causes depolarisation/hyperpolarisation of the cell causing cellular responses
- Takes milliseconds to respond
- Example: nicotinic receptors
Outline the structure of metabotropic receptors (i.e G-protein coupled receptors)
- 7 transmembrane regions
- Induce secondary physiological responses through activation of a G-protein e.g phosphorylation, release of calcium ions, enzyme activation/inhibition, opening of other ion channels
- Takes seconds to respond - time needed for response by secondary messenger
- Example: muscarinic receptors
Outline the definition of the following words
- AGONIST
- ANTAGONIST
- AGONIST - a drug that binds to a receptor through which a biological response is elicited
- ANTAGONIST - a drug that binds to the receptor without a biological response - usually to prevent another agonist binding and eliciting a response
What is a partial agonist?
Produces a biological response, but not as maximal as what a tissue is capable of
- High affinity but reduced efficacy
What is an inverse agonist?
Agonist that binds to receptor and causes an opposing biological response to that observed from a full agonist e.g causing an increase in ion concentration rather than a decrease
Outline the difference between affinity and efficacy
- Affinity refers to the ability of a drug to occupy and bind to a receptor to form a drug-receptor complex (A+R ⇌ AR) e.g how strong is binding?
- Efficacy refers to the ability to elicit a biological response from a drug-receptor interaction (AR ⇌ AR* –> RESPONSE)
- Agonists will have both affinity and efficacy
How do agonists usually bind to receptors? Outline the four ways in which binding may occur and their significance
- Agonists usually bind reversibly to receptors and then dissociate
REVERSIBLE BINDING
- Hydrogen bonding
- Van der Waals forces
- Ionic bonding
- SIGNIFICANCE - relatively weak attractions - can reversibly bind and dissociate
IRREVERSIBLE BINDING
- Covalent bonding
- SIGNIFICANCE - relatively strong attraction - poor dissociation
Outline the steps that would be taken when doing a binding assay
- First identify where the receptors are found
- Add drug in increasing concentrations
- Once added, for each concentration , measure the amount of drugs found bound to receptors
- This allows a saturation curve to be plotted - with concentration of ligands added on x-axis and concentration of bound ligands on y-axis
What parameters can be determined from a saturation plot?
- Bmax - maximum concentration of ligands bound to receptors
- Kd - concentration of drug needed to reach half of Bmax - to occupy half of the receptor population. This is inversely proportional to affinity. Lower Kd - higher affinity.
What does the Law of Mass Action predict?
Agonist + Receptor ⇌ Agonist-Receptor Complex
- Low concentration of the agonist and lots of free receptors, then there will be few AR interactions.
- Increase the agonist concentration, more AR interactions, so the reaction will be driven to the right.
- Continue increasing the agonist concentration, the reaction reaches its maximal due to finite number of receptors
What is meant by Ka?
- Concentration of the agonist when half of the maximum number of receptors are bound by the drug
- Lower Ka - higher affinity for receptor by agonist compared to drug with higher Ka. Unique for each drug
What are the ‘measurements’ of efficacy?
- Threshold concentration - minimum concentration for which a biological response is produced
- EC50: effective concentration, giving 50% of the biological response (found when you take half of the maximal concentration). Higher EC50, lower efficacy
- Maximal concentration (at the point when the plot completely saturates)
True or false - the maximal concentration will produce maximal efficacy
FALSE
- Only need a small amount of drug-receptor interactions because the receptors amplify the signal
What is meant by potency?
- Measure of the concentration of drug needed to produce a response
- Lower concentration needed - more potent drug
Order the following in terms of efficacy
- AGONIST
- PARTIAL AGONIST
- ANTAGONIST
AGONIST - high efficacy
PARTIAL AGONIST - some efficacy
ANTAGONIST - no efficacy
Considering that Buprenorphine is a partial agonist, suggest how it can be used to treat opioid addiction.
- High affinity for heroin receptors and so bind to them
- Prevent binding of heroin to these receptors
- Reduced withdrawal effects - as no biological response elicited due to prevented binding of heroin
What is meant by competitive antagonism?
- Both agonists and antagonists can reversibly bind to receptors and so compete for the same binding site
AGONIST OR ANTAGONIST + RECEPTOR ⇌ AGONIST-RECEPTOR COMPLEX + ANTAGONIST- RECEPTOR COMPLEX - Equilibrium constants KA and KAnt influence the reaction
- If KAnt < KA, antagonist has higher affinity for receptors than agonist and binds. This is because a lower antagonist concentration is required to bind to receptors than agonists
- This is countered by increasing agonist concentration
What effect does competitive antagonism have on saturation plots and how does it prove that antagonism is ‘surmountable’?
- When antagonist added, curve is shifted to right and the linear region of the curve remains parallel
- Maximal response is not affected
- This is because by increasing agonist concentration, the antagonist can be ‘outcompeted’ allowing the agonist to bind and cause a biological response hence the antagonism can be ‘surmounted’
What is meant by the following term
- non surmountable antagonism
- Non-surmountable antagonism is when the antagonist cannot be outcompeted by increasing the agonist concentration. As a result, agonist+antagonist does not reach the same maximal response as an agonist normally would.
How does aspirin work to inhibit COX activity?
- Acetyl group forms a covalent bond with active site of enzyme
- Reduced binding to receptor
What is non-competitive antagonism?
- Antagonist binds to a separate binding site away from the receptor, causing a conformational shape change in the receptor.
- The agonist can no longer bind to the receptor, and this also reduces the number of receptors present for binding, contributing to a reduced biological response.
What is irreversible antagonism?
- Antagonist binds to the agonist or a separate non-agonist binding site through covalent bonding
- Reduces the number of receptors the agonist can bind to by inducing conformational changes in the receptor.
