Receptor-Ligand Interactions Quiz

Receptor-Ligand Interactions

• Drug interactions are similar to enzyme-substrate interactions
• Drugs only work when they bind to a target
• Many drugs bind to receptors

Receptors and Enzymes

• Drug + target = Effect
• Ligand + receptor = Modified receptor
• Substrate + enzyme = Modified substrate

What is a Receptor?

• Receptors have affinity for ligands
• Limited number of receptor binding sites, making them saturable and finite
• Receptors are not evenly distributed throughout the body
• Agonist binding causes a physiological response
• Receptors can generate different physiological responses in different tissues

Ligand Selectivity

• Selectivity is defined as relative affinity of a ligand for a receptor
• Ligand-receptor binding is not completely specific and can lead to off-target binding at higher concentrations
• Example: Beta 1 and Beta 2 receptors in the cardaic system: Beta 1 receptors increase heart rate while Beta 2 receptors increase coronary flow

The Dose-Response Relationship

• Tissue responses are directly proportional to the fraction of receptors occupied by an agonist
• The more receptors occupied, the stronger the signaling response
• Dose-response curve: a graph showing the relationship between the dose of a drug and its effect, measured in units of effect (e.g., heart rate)
• ED50: the dose that produces 50% of the maximum effect

Linear vs. Log Dose-Response Curves

• Linear scale: a dose-response curve where the dose and response are plotted on a linear scale
• Log scale: a dose-response curve where the dose is plotted on a logarithmic scale, making it easier to see the relationship between the dose and response at low doses

Assessing Drug Interactions with Receptors

• Functional Studies: Measure tissue response to a drug
• Binding Studies: Measure the binding of a radiolabeled drug to tissue
• Assumptions for binding studies:
  • Ligands bind specifically and reversibly
  • Binding is saturable and reversible
  • All receptors are equally accessible to ligands
  • Receptors are either bound or unbound

Saturable Binding: Principles

• Total binding: the amount of radiolabeled ligand that binds to the tissue
• Specific binding: the amount of radiolabeled ligand that binds specifically to the receptor
• Non-specific binding: the amount of radiolabeled ligand that binds non-specifically to other sites in the tissue
• Measurement of specific binding is obtained by subtracting nonspecific binding from total binding

Competition Binding

• A method for measuring the affinity of a ligand for a receptor
• Involves adding one concentration of radioligand and then displacing the radioligand with an unlabeled ligand
• Affinity is calculated based on concentration of radioligand and relative affinities of unlabeled (cold) and labeled ligands

Drug Potency

• Potency: A measure of the drug's activity expressed as the amount of drug required to produce an effect
• ED50: The dose of a drug that produces 50% of its maximum effect
• Example: Drug A has a lower ED50 than Drug B, meaning less of Drug A is needed to produce the same effect as Drug B.

Efficacy/Intrinsic Activity

• Efficacy: The ability of a drug to produce a response (how well it works)
• Intrinsic activity: Similar to efficacy
• Full agonist: a drug that produces the maximum possible response when it binds to a receptor
• Partial agonist: a drug that produces a response less than the maximum possible response, even when it binds to all of the receptors.

Partial Agonists vs. Full Agonists

• Partial Agonists: bind to the same receptor as a full agonist, but with a reduced ability to activate signaling pathways or induce conformational change.
• Full Agonists: bind to the same receptor with sufficient affinity to cause a maximal signal and induce a change in the conformation of the receptor
• Partial agonist example: Buprenorphine, a drug used to treat opioid addiction, is a partial agonist of mu opioid receptors

Spare Receptors

• Occurs when maximum signaling response is observed without all receptors being occupied
• Suggests that not all receptors need to be occupied to produce the maximum response
• Presence of spare receptors can increase tissue sensitivity to agonists

Potency vs. Efficacy

• Potency: Measures the drug's strength (ED50)
• Efficacy: Measures how well the drug works (intrinsic activity)

1. New Terminology:

• Ligand: A molecule that binds to a target
• Agonist: A ligand that binds to a receptor and causes a response:
  • Full agonist: produces the maximum response
  • Partial agonist: produces a response less than the maximum
• Antagonist: A ligand that blocks the action of an agonist

2. New Terminology

• Affinity: The ability of a ligand to bind to its target
  • Kd: The equilibrium dissociation constant, a measure of affinity
• Dose: The amount of a drug given
  • ED50: The dose that produces 50% of the maximum effect
• Concentration: The amount of substance per unit volume
  • EC50: The concentration of a drug that produces 50% of the maximum effect
  • IC50: The concentration of a drug that inhibits 50% of a response
• Potency: A measure of how much drug is needed to produce a given effect
• Efficacy/Intrinsic Activity: A measure of how well a drug produces its maximum effect (usually expressed as a fraction of the maximum response)
  • Partial agonists: Produce a response less than the maximum
• Spare Receptors: The presence of receptors that are not needed to produce the maximum response

What We Have Learned:

• Ligands: Molecules that bind to a target
• Receptors: Molecules that bind ligands and initiate a signaling response
• Agonists: Ligands that activate receptors (full and partial agonists)
• Dose-response relationships: Demonstrate the relationship between the dose of a drug and its effect
• Quantitative concepts: Kd, Bmax, IC50, and EC50, which quantify the affinity of a drug for its target and the potency and efficacy of a drug

Receptor-Ligand Interactions

• Drug action requires binding to a target, similar to enzyme-substrate interactions.
• Paul Ehrlich (1913) stated that drugs do not work unless they are bound.
• Many drugs exert their effects by binding to receptors.

Receptors and Enzymes

• Drug + Target → Effect
• Ligand + Receptor → Modified receptor, activation
• Substrate + Enzyme → Modified substrate

What is a Receptor?

• Receptors possess affinity for specific ligands.
• Receptors are saturable and finite, meaning they have a limited number of binding sites.
• Receptors are discontinuously distributed within the body.
• Agonist binding to a receptor causes a biological response.
• The same receptor can trigger different physiological responses in different tissues.

Ligand Selectivity

• Selectivity refers to the relative affinity of a ligand for a specific receptor.
• Ligand-receptor binding is not always specific, and a ligand can bind to other receptors at higher doses.
• This lack of specificity influences the therapeutic index of the drug.

The Dose-Response Relationship

• Tissue responses are directly proportional to the fraction of receptors occupied by an agonist.
• The more receptors occupied, the stronger the signaling response.
• The dose-response curve illustrates the relationship between drug concentration and the magnitude of effect.
• The ED50 (effective dose 50) is the concentration of the drug that produces 50% of its maximal effect.

Linear Versus Log Dose-Response Curves

• A linear scale shows a direct relationship between dose and response.
• A logarithmic scale emphasizes the initial steep slope of the curve, highlighting the rapid change in response at lower doses.

Assessing Drug-Receptor Interactions

• Functional studies measure the response of a tissue to a drug.
• Binding studies directly measure the binding of radiolabeled drugs to tissues.
• Assumptions for binding studies:
  • Ligands bind specifically and reversibly to receptors.
  • Binding is saturable and reversible.
  • Receptors are equally accessible to ligands.
  • Receptors are either free or bound to a drug.

Saturation Binding Principles

• Radiolabeled ligands bind to receptors.
• Non-specific binding occurs independently of the target receptor.
• Specific binding represents the binding to the receptor of interest.
• Specific binding saturates as all available receptor sites are occupied.

Competition Binding

• Non-radiolabeled ligands compete with the radiolabeled ligands for binding to the receptor.
• The competition binding is used to determine the affinity of the non-radiolabeled ligand.

Potency

• Potency refers to the amount of drug required to produce a specific effect.
• ED50 values can be used to compare the potency of drugs.
• A lower ED50 indicates greater potency.

Partial Agonists

• Partial agonists have an efficacy (or intrinsic activity) greater than zero but less than one.
• They can bind to and activate receptors, but they produce a weaker response compared to full agonists.

Full Versus Partial Agonists

• Full agonists induce a maximal response, while partial agonists induce a reduced response.
• The difference lies in the conformational change induced by the agonist.

Spare Receptors

• Maximum signaling responses can be achieved without full receptor occupancy.
• Spare receptors increase the tissue sensitivity to agonists.

Efficacy Versus Potency

• Efficacy refers to the ability of a drug to produce a therapeutic effect, while potency refers to the amount of drug needed to produce that effect.
• A drug with a high efficacy can produce a large effect, even if the drug is not very potent.
• A drug with a low efficacy can only produce a small response, even if it is potent.

Terminology Summary

• Ligand: A molecule that binds to a target, including receptors.
• Agonist: A ligand that activates a receptor, triggering a specific biological response.
  • Full agonists produce the maximal response.
  • Partial agonists produce a weaker response.
• Antagonist: A ligand that binds to the receptor but does not activate it, blocking the action of agonists.
• Affinity: The tendency of a ligand to bind to its target.
• Dose: The amount of drug administered.
• Concentration: The amount of drug per unit volume.
• Potency: The amount of drug required to produce a specific effect.
• Efficacy/Intrinsic Activity: The ability of a drug to produce a response at its receptor, irrespective of potency.
• Spare Receptors: Excess receptors that provide a reserve capacity, influencing sensitivity.

Receptor-Ligand Interactions

• Drug interactions with receptors are analogous to enzyme-substrate interactions
• "Drugs do not act unless bound" - Paul Ehrlich, 1913.

Receptors & Enzymes

• Drug + Target = Effect
• Ligand + Receptor = Modified Receptor
• Substrate + Enzyme = Modified Substrate

What is a Receptor?

• Receptors possess affinity for ligands.
• Receptors are saturable and finite (limited number of binding sites).
• Receptors are discontinuously distributed.
• Agonist binding to a receptor causes a response.
• The same receptor may generate a different physiological response in different tissues.

Ligand Selectivity

• Selectivity is defined as relative affinity.
• Ligand-receptor binding is not specific. A ligand will bind to other receptors as the dose/concentration is increased.

Dose-Response Relationships

• Tissue responses are generally directly proportional to the fraction of the receptors occupied with agonist.
• Dose-Response Curve: ED50 (Effective Dose 50) is the concentration of drug that produces 50% of the maximal response.

Linear vs Log Dose-Response Curves

• Linear Scale: Linear relationship between dose and response.
• Log Scale: Sigmoidal curve demonstrating a threshold dose, ED50, and maximum response.

Saturation Binding Analysis

• Radioactive ligand binds to a receptor protein.
• Specific Binding: Binding to the receptor (saturable)
• Non-specific Binding: Non-saturable
• Total Binding = Specific Binding + Non-specific Binding
• KD (Dissociation Constant): Concentration of radioligand at which 50% of the receptors are occupied.

Competition Binding Analysis

• A fixed concentration of radioligand competes with unlabelled ligand for binding to the receptors.
• IC50 (Inhibitory Concentration 50): Concentration of unlabelled ligand required to inhibit 50% of the radioligand binding.

Drug Potency

• Potency is a measure of drug activity, expressed as the amount required to produce a given effect.
• ED50 is used to compare the potency of different drugs.

Full vs Partial Agonists

• Full Agonist: Produces maximum response when bound to the receptor.
• Partial Agonist: Produces a submaximal response, even when bound to all available receptors.

Efficacy & Intrinsic Activity

• Efficacy / Intrinsic Activity (α): Ability to produce a response.
• Full Agonist - α = 1
• Partial Agonist - 1 > α > 0
• Antagonist - α = 0

Spare Receptors

• Spare receptors are receptors that are not bound by agonist when maximum response is achieved.
• Presence of spare receptors contributes to increased tissue sensitivity to agonists.

Potency vs Efficacy

• Potency: Amount of drug required to produce an effect (indicated by ED50).
• Efficacy: Maximum effect the drug can produce (indicated by the height of the dose-response curve).

Summary Terminology

• Ligand: Binds to its target.
• Receptor: Next week's lecture.
• Agonist:
  • Full Agonist: Produces a maximal response.
  • Partial Agonist: Produces a submaximal response.
• Antagonist: Next lecture.

Affinity

• Affinity: The ability to bind a target.

Dose vs Concentration

• Dose: Amount given.
• Concentration: Amount per unit volume.

Additional Summary Terminology

• ED50: Effective dose 50
• EC50: Effective Concentration 50
• IC50: Inhibitory Concentration 50
• Potency (Defined by ED50)
• Efficacy/Intrinsic Activity
• Partial Agonists
• Spare Receptors