Drug Receptor Interactions

Question 1

Explain the importance of understanding receptors

Answer 1

• 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

Question 2

Outline the structure of ionotropic receptors (i.e ion channel receptors)

Answer 2

• 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

Question 3

Outline the structure of metabotropic receptors (i.e G-protein coupled receptors)

Answer 3

• 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

Question 4

Outline the definition of the following words
- AGONIST
- ANTAGONIST

Answer 4

• 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

Question 5

What is a partial agonist?

Answer 5

Produces a biological response, but not as maximal as what a tissue is capable of
- High affinity but reduced efficacy

Question 6

What is an inverse agonist?

Answer 6

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

Question 7

Outline the difference between affinity and efficacy

Answer 7

• 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

Question 8

How do agonists usually bind to receptors? Outline the four ways in which binding may occur and their significance

Answer 8

• 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

Question 9

Outline the steps that would be taken when doing a binding assay

Answer 9

• 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

Question 10

What parameters can be determined from a saturation plot?

Answer 10

• 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.

Question 11

What does the Law of Mass Action predict?

Answer 11

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

Question 12

What is meant by Ka?

Answer 12

• 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

Question 13

What are the ‘measurements’ of efficacy?

Answer 13

• 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)

Question 14

True or false - the maximal concentration will produce maximal efficacy

Answer 14

FALSE
- Only need a small amount of drug-receptor interactions because the receptors amplify the signal

Question 15

What is meant by potency?

Answer 15

• Measure of the concentration of drug needed to produce a response
• Lower concentration needed - more potent drug

Question 16

Order the following in terms of efficacy
- AGONIST
- PARTIAL AGONIST
- ANTAGONIST

Answer 16

AGONIST - high efficacy
PARTIAL AGONIST - some efficacy
ANTAGONIST - no efficacy

Question 17

Considering that Buprenorphine is a partial agonist, suggest how it can be used to treat opioid addiction.

Answer 17

• 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

Question 18

What is meant by competitive antagonism?

Answer 18

• 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

Question 19

What effect does competitive antagonism have on saturation plots and how does it prove that antagonism is ‘surmountable’?

Answer 19

• 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’

Question 20

What is meant by the following term
- non surmountable antagonism

Answer 20

• 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.

Question 21

How does aspirin work to inhibit COX activity?

Answer 21

• Acetyl group forms a covalent bond with active site of enzyme
• Reduced binding to receptor

Question 22

What is non-competitive antagonism?

Answer 22

• 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.

Question 23

What is irreversible antagonism?

Answer 23

• 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.