lecture 3- agonists and antagonists

Q: What is a ligand?

A: Any chemical that binds to a receptor.

Q: What is an agonist?

A: A drug that binds to a specific site on a receptor and mimics the effect of the endogenous ligand for that site.

Q: What is an antagonist?

A: A drug that binds to a specific site on a receptor and blocks the effect of the endogenous ligand (same or different binding site as ligand).

Q: What is the lock and key concept?

A: Receptor is the lock, endogenous ligand (e.g. hormone) is the key.

Q: How does an agonist act in the lock and key concept?

A: An agonist drug fits into the lock; mimics the action of the key; can be used to pick the lock and activate the receptor.

Q: How does an antagonist act in the lock and key concept?

A: An antagonist drug also fits into the lock; gets stuck and prevents opening of the lock (i.e. activation of the receptor) by either endogenous ligand or agonist. (See diagram on slide)

Q: What do agonists do?

A: Agonists bind to receptors and activate them. (See diagram on slide)

Q: What two properties do agonists possess?

A: Agonists possess both affinity and efficacy.

Q: What is affinity? DIAGRAM

A: Affinity is a measure of the strength of association between ligand and receptor.

Q: What does high affinity mean?

A: Binds quickly and dissociates slowly → stays bound longer.

Q: What does low affinity mean?

A: Binds slowly and dissociates quickly → spends less time bound.

Q: What is efficacy? DIAGRAM

A: Efficacy is a measure of the ability of an agonist to evoke a (cellular) response.

Q: What is the difference between high and low efficacy?

A: High efficacy: Produces a larger receptor response. Low efficacy: Produces a smaller receptor response.

Q: What is important about drug-receptor interactions?

A: Drugs are constantly binding and unbinding, and receptors are being activated and deactivated — it is a dynamic process.

Q: How does receptor occupancy change with increasing agonist concentration?

A: Receptor occupancy increases with increasing agonist concentration. Not a linear relationship! (See diagram on slide)

Q: Do you need to occupy 100% of a receptor to see a maximal response?

A: No.

Q: What is the relationship between concentration (or dose) and response?

A: Relationship between concentration (or dose) and response is hyperbolic. (See diagram on slide)

Q: What is EC50?

A: EC50 is the concentration of an agonist that elicits half-maximal response.

Q: Why is EC50 important?

A: Important efficacy measure that allows comparison between drugs.

Q: What happens when the same data is plotted on a semi-log scale?

A: Relationship is sigmoidal; easier to calculate EC50. (See diagram on slide)

Q: Why is it easier to plot a log concentration-response curve rather than a concentration-response curve?

A: Because the relationship becomes sigmoidal, making it easier to determine/calculate the EC50.

Q: What is the difference between potency and efficacy?

A: Potency relates to the concentration needed for an effect; efficacy relates to the magnitude of the effect.

Q: What does a lower EC50 indicate about potency?

A: The lower the EC50, the more potent the drug is.

Q: How do Drug A and Drug B compare?

A: Drug A and Drug B are full agonists. Drug A is more potent than Drug B but has equal efficacy. (See diagram on slide)

Q: How do Drug A and Drug C compare?

A: Drug A & Drug C have the same potency (equipotent; EC50 is the same).

Q: What type of agonist is Drug C?

A: Drug C is a partial agonist that has lower efficacy than either Drug A or Drug B. (See diagram on slide)

Q: What do antagonists do?

A: Antagonists bind to receptors but DO NOT activate them.

Q: What properties do antagonists possess?

A: Antagonists possess affinity but they lack efficacy.

Q: What do antagonists block?

A: Antagonists block receptor activation by agonists. (See diagram on slide)

Q: What is a competitive antagonist?

A: Binds to the same site as the agonist (or endogenous ligand).

Q: What happens during competitive antagonism?

A: Competes with the agonist / endogenous ligand for binding.

Q: What determines the ‘winner’ in competitive antagonism?

A: Concentrations and affinities of agonist / antagonist determines the ‘winner’.

Q: Can the effect of a competitive antagonist be overcome?

A: Effect of antagonist can be overcome by increasing agonist concentration.

Q: What is a non-competitive antagonist?

A: Binds to a site that is distinct from the agonist binding site.

Q: How does a non-competitive antagonist affect the receptor?

A: Causes change in conformation of receptor that restricts agonist binding.

Q: Can the effect of a non-competitive antagonist be overcome?

A: Effect of antagonist cannot be overcome by increasing agonist concentration.

Q: What happens to the maximum agonist response with competitive antagonists?

A: Maximum agonist response can still be achieved in the presence of competitive antagonists by increasing agonist concentration. (See diagram on slide)

Q: What happens to the maximum agonist response with non-competitive antagonists?

A: Maximum agonist response cannot be achieved in the presence of non-competitive antagonists, no matter how much agonist is present. (See diagram on slide)

Q: What are different types of competitive antagonism?

A: Some competitive antagonists bind covalently (i.e. irreversibly) to agonist binding site; not displaced by agonists, extent of antagonism depends on receptor occupancy.

Q: What happens with reversible competitive antagonism?

A: Effect of a reversible competitive antagonist can be overcome by increasing agonist concentration, even at high antagonist concentrations; maximal response still reached. (See diagram on slide)

Q: What happens with irreversible competitive antagonism?

A: Effect of an irreversible competitive antagonist is not overcome, even at high agonist concentrations; maximum response not achieved; behaves like non-competitive antagonist. (See diagram on slide)

Q: What happens when an agonist occupies the receptor (R)?

A: Drug A is an agonist; when it occupies the receptor (R), the receptor tends to become activated. (See diagram on slide)

Q: What happens when an antagonist occupies the receptor?

A: Drug B is an antagonist: receptor occupation does not lead to activation.

Q: What do the rate constants k+1, k−1, α and β represent?

A: Rate constants k+1, k−1, α and β vary between drugs.

Q: What is β for an antagonist?

A: For an antagonist, which does not activate the receptor, β = 0.

Q: What is important about receptor occupation and activation?

A: For most drugs, occupation and activation are reversible, dynamic processes.

Q: What are the two conformational states in the two-state model?

A: Most receptors exist in two conformational states, resting (R) and activated (R*). (See diagram on slide)

Q: What happens in the absence of an agonist?

A: In the absence of agonist, the equilibrium lies to the left (i.e. most receptors are resting).

Q: What do full agonists do?

A: Full agonists bind preferentially to R* - shift equilibrium to the right.

Q: What does higher agonist affinity for R* mean?

A: Higher agonist affinity for R* = greater efficacy.

Q: How do antagonists affect the two-state equilibrium?

A: Antagonists have equal affinity for R and R* - do not shift the equilibrium.

Q: How do antagonists prevent equilibrium shifts?

A: Antagonists affect the ability of other drugs to bind to R or R*; prevent equilibrium shifts.

Q: What are constitutively active receptors?

A: Some receptors are “constitutively active” (e.g. cannabinoid or CB1 receptors).

Q: What is different about constitutively active receptors?

A: In the absence of agonist, an appreciable proportion of these receptors are in the R* state. (See diagram on slide)

Q: What do inverse agonists do?

A: Inverse agonists bind preferentially to R and shift equilibrium to the left.

Q: What is the effect of an inverse agonist?

A: Switch receptor activation off and reduce response.

Q: What does higher inverse agonist affinity for R mean?

A: Higher inverse agonist affinity for R = greater efficacy.

Q: What do antagonists do to agonists and inverse agonists?

A: Antagonists block agonists and inverse agonists equally.

Q: What are partial agonists?

A: Partial agonists have a lower maximum response (i.e. lower efficacy) than full agonists.

Q: When are the true effects of partial agonists seen?

A: True effects of partial agonists are only seen in the absence of full agonists.

Q: What do partial agonists look like in the presence of full agonists?

A: In the presence of full agonists, partial agonists look like competitive antagonists.

Q: When are the true effects of inverse agonists seen?

A: True effects of inverse agonists are only seen when receptor is constitutively active.

Q: What do inverse agonists look like in the absence of constitutive activity?

A: In the absence of constitutive activity, inverse agonists also look like competitive antagonists.

Q: How does the volume knob analogy explain agonists and antagonists?

A: A full agonist turns the volume from zero to ten on regular receptors and from five to ten on constitutively active receptors. A partial agonist turns the volume from zero to five on regular receptors and from five to eight on constitutively active receptors. An inverse agonist turns the volume from five to zero, while an inverse partial agonist turns it from five to two. A competitive antagonist is like a stiff volume knob, while a non-competitive antagonist is like a broken volume knob. (See diagram on slide)

Q: What are allosteric modulators?

A: Allosteric modulators bind at distinct site to affect affinity and/or efficacy of agonists.

Q: What are the two types of allosteric modulators?

A: Can be positive allosteric modulators (PAMs) or negative allosteric modulators (NAMs).

Q: What can NAMs look like?

A: NAMs can look like competitive antagonists (affinity) or non-competitive antagonists (efficacy).

Q: What do PAMs do?

A: PAMs make volume knob easier to turn (affinity) or ‘turn up to eleven’ (efficacy). (See diagram on slide)

Q: What are receptors typically coupled to?

A: Receptors are typically coupled to effector mechanisms that elicit the response following agonist binding.

Q: What is important about some receptors?

A: Some receptors coupled to more than one effector mechanism.

Q: What is conventional agonism?

A: Different agonists bind to same receptor and activate effector mechanisms to the same extent. (See diagram on slide)

Q: What is biased agonism?

A: Different agonists bind to the same receptor and preferentially activate one effector mechanism. (See diagram on slide)

Q: What is a partial agonist?

A: A low efficacy agonist that is unable to elicit the maximal response from a receptor, irrespective of the concentration applied.

Q: What is an inverse agonist?

A: A compound that binds to the same receptor site as an agonist but produces the opposite effect (constitutively-active receptors only).

Q: What is an allosteric modulator?

A: A compound that binds to a receptor site distinct from the agonist binding site, inducing a conformational change that alters the affinity or efficacy of agonist binding (at the orthosteric site).

Q: What is affinity?

A: A measure of the equilibrium constant of the reversible reaction between a drug (agonist or antagonist) and a receptor.

Q: What is efficacy?

A: A measure of the magnitude of the (cellular) response produced when an agonist binds to a receptor.

Q: What is potency?

A: A measure of the concentration of a drug at which it produces an effect of a given magnitude.

Q: What is specificity?

A: A measure of the range of receptor sites that a given drug may bind to or the range of effects it may produce.

Q: What is selectivity?

A: The degree to which a drug binds to a given receptor site relative to other receptor sites (related to affinity).

Q: What do agonists and antagonists do?

A: Agonists bind to receptors and activate them; antagonists bind to receptors but do not activate them (block effect of agonists).

Q: What does receptor occupancy and biological response reflect?

A: Receptor occupancy and biological response reflects agonist concentration; the efficacy of an agonist reflects the magnitude of its effect (full or partial).

Q: What does the potency of an agonist reflect?

A: Potency of an agonist reflects the concentration at which it produces an effect of specific magnitude.

Q: What types of antagonists are there?

A: Antagonists can be competitive or non-competitive; based on binding site and influence of increasing agonist concentration; can also be irreversible.

Q: What do inverse agonists and allosteric modulators do?

A: Inverse agonists have opposite effects to agonists; allosteric modulators influence affinity and/or efficacy of agonists.

Q: What do biased agonists do?

A: Biased agonists preferentially activate one effector mechanism over another.

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