Ligand Receptor Interactions: Key Concepts

• These notes cover drug stimulus-response, dose-response curves, variability in drug response, the therapeutic index, certain safety factors, PK/PD simulations, and related topics.

Drug Affinity, Efficacy, and Mechanism of Action

• Pharmacology models of drug discovery involve examining drug affinity, efficacy, and mechanism of action.
• Models aim to predict activity in different receptor systems and to determine appropriate drug dosage for a therapeutic system.
• Models address how a drug will behave in vivo with an endogenous ligand and if the observed response will be therapeutically relevant.

Drug Targets

• Drug targets are often located on cells, such as transmembrane receptors.
• Receptors facilitate communication from outside to inside the cell.
• The intracellular receptor region transmits a signal.
• Receptors on the membrane bind drugs, initiating communication within the cell.
• Variability arises from different receptors, subunits, and isoforms.
• Molecules can affect cell function in the cytosol or on the membrane surface.
• Specific receptor subtypes include G-protein coupled receptors and ion channels.

Ligand Stimulus-Response in Cells

• The equation D (drug) + R (receptor) ↔ Drug-Receptor complex represents drug-receptor interaction.
• The drug-receptor interaction goes inside the cell.
• A drug causes a conformational change for the stimulus to become a response.
• Chemicals bind to extracellular sites, affecting signaling molecules inside the cell.
• A biochemical reaction to some endpoint or response is a crucial stage.
• Ligand stimulus-response is related to drug efficacy.

Dose-Response Curves

• Drugs bind and produce a response, reflecting the drug's intrinsic efficacy.
• Graphs of dose-response curves illustrate slope and different values.

Transmembrane Receptor Structure

• Helices form a ternary complex in transmembrane receptors.
• Protein helices translate from extracellular to intracellular portions.
• The receptor binds drugs/ligands and elicits a response inside the cell.
• The arrangement of peptide chains defines molecular structure.
• There are seven transmembrane structures.
• Ion channels have a pore that opens and closes to allow ions to transduce through.
• Receptors are dynamic and undergo conformational changes that control signaling within a cell.
• Efficacy is defined as a molecule's ability to change a receptor to produce a cellular response.
• Ligands can be biased to a certain conformation, stabilizing it and demonstrating intrinsic efficacy.

Receptor Conformation

• The basal state is the normal, non-activated state of a receptor.
• Receptors have multiple conformations, with a major conformation in the basal state.
• Inactive receptors can come into equilibrium with activated receptors.
• Adding a ligand/drug shifts the binding of the basal state to activated receptors, with the drug preferring an active conformation to elicit a response, ultimately enriching the population of active receptors.
• Conformations change from basal to active states.
• Graphs of receptor conformation plot stimulus (Y-axis) against the concentration of an agonist or ligand (X-axis), where agonists elicit different stimulus-responses.
• Agonist #2 elicits a higher stimulus than agonist #1.

Dose-Response

• Graphs of dose-response plot response (Y-axis) against concentration (X-axis).
• Agonist #2 provides a higher stimulus at less concentration, and is therefore, more potent.
• Rank order: Agonist #2 > Agonist #1.
• Agonist #2 is more potent.

Dose-Response Curves: Characteristics

• Maximal efficacy (Emax) is the largest response elicited by the drug.
• Potency is the drug concentration that causes a response.
• Slope indicates the variation from low to maximal response.
• Individuals can respond differently to the same dose.

Maximal Efficacy

• Maximal efficacy (Emax) is the maximal response of a drug.
• Clinical usefulness depends on a drug's efficacy in a patient population.
• The choice of drug depends on the indication, indicating that some indications require higher efficacy than others.

Potency and EC50

• EC50 is the drug concentration that causes a half-maximal response.
• The 50% point is easy to find on a dose-response curve.
• It is used to compare different drug potencies.

Slope and Law of Mass Action

• Slope determines whether a drug follows the law of mass action.
• The law of mass action states that 80% of the response occurs over a hundredfold increase in dose.
• EC50 is defined as 50%.
• A normal dose-response curve follows the law of mass action.
• A steep slope indicates positive cooperativity or spare receptors.
• A shallow slope indicates negative cooperativity or multiple receptors.

Log Scales

• Log scales facilitate the measurement of EC50, Emax, and slope over large ranges of drug concentrations.
• Log scales allow a greater range of concentrations to fit on one curve.
• Log scales make it easier to see baseline, slope, and maximal efficacy.
• Lower EC50 value indicates a more potent drug.
• Drugs can be equally efficacious even if one is less potent.
• Potency matters in cases of drug-drug interactions or when side effects are a concern.

Partial Agonists

• A partial agonist does not reach the same efficacy/Emax as a full agonist.
• In the case of a partial agonist, the EC50 is determined relative to the maximal effect of the partial agonist.

Comparing Drug Potency and Efficacy

• A drug can be more potent but less efficacious, or vice versa.
• Information about binding is needed to understand if drugs are binding the same receptor.
• Practice graphing and extracting values from dose-response curves.

Drugs with Similar Mechanisms of Action

• Drugs with similar mechanisms of action exhibit parallel dose-response curves.
• They follow the law of mass action.

Drugs with Different Mechanisms of Action

• Drugs with different mechanisms of action can have different maximal efficacies and slopes.
• Steeper or shallower slopes indicate binding to different drug populations.
• Different mechanisms of action cause different dose-response patterns.

Partial Agonists (Tramadol)

• Bind to the same opioid receptors as morphine and fentanyl but don't fully activate them.
• Receptor occupancy information is needed to determine if a drug is a partial agonist versus a different mechanism of action.

Stimulus-Response Relationship

• Drug-receptor interaction (binding) leads to a conformational change (stimulus), producing a response.
• Different drug-receptor interactions can cause the same response but bind different targets.
• Curves define receptor occupancy, dependent on intrinsic efficacy and the number of receptors.
• Dose-response curves differ from binding curves and receptor occupancy.

Preclinical Realm

• Graded responses in cells, tissues, and animals.
• Determination of maximal response and effective concentration at 50% (EC50).
• Examples: Muscle tissue measuring force and lengthening changes with drug addition.
• Cells: Measuring cell viability and death with anti-cancer drugs.
• Patient Response: More commonly an all-or-none response due to set thresholds.
• Values obtained are slightly different from EC50 values.

Receptor Occupancy

• Receptor occupancy is the amount of drug that binds to a specific receptor target.
• Bmax: Maximal binding.
• KD Value: Half-maximal biding, indicating affinity for the target.

Affinity vs. Potency

• Occupancy and Receptor Target: Affinity to the target.
• Response: Potency for the drug response.

Variability in Patient Response

• Patient Variation: Patients respond differently to the same dose of a drug.
• Pharmacogenomic Differences: Understanding genetic makeup helps predict responders vs. non-responders.

Drug Efficacy

• Beneficial and Non-Toxic: The desired outcome.
• Toxic and Non-Beneficial: Undesirable outcome.
• Non-Toxic and Non-Beneficial: Ineffective drug.
• A larger population group may exhibit side effects not seen in smaller populations.

PK/PD Responses

• Variability is divided into pharmacokinetic and pharmacodynamic responses.
• Pharmacokinetic (PK): what the body does to the drug i.e. absorption, excretion, metabolism, impacted by factors like stomach contents, skin texture (for topical applications) and CYP enzymes.
• Pharmacodynamic (PD): what the drug does to the body i.e. drug binding to a target, including conformational changes, triggering signaling pathways, influenced by receptor numbers, receptor subtypes, and concentrations of endogenous compounds.
• Pharmacogenomic single-nucleotide polymorphisms contribute to variation in PD and PK.

Pharmacokinetic Variability

• ADME Profiling: Absorption, Distribution, Metabolism, Elimination.
• Absorption: Varied by stomach contents and skin texture.
• Distribution: Depends on protein binding and body composition.
• Metabolism: Can vary with hepatic function, age ,and CYP enzyme variations.
• Elimination: Can vary with kidney function, age.

Pharmacodynamic Variability

• Receptor Number: More or less receptors available affect the response.
• Receptor Subtype: Different receptors cause variance in response.
• Signal Transduction: Different signaling pathways can influence variability.
• Compensatory Mechanisms: Hormonal balances.
• Patient Characteristics and Variability is affected by body weight, body composition, age, gender, disease state, and genetics.

Body weight

• Lipid binding, leptin release.
• Impacts drug compartmentalization and the lean-to-fat ratio.

Body Composition

• Amount of lipid stores.
• Body composition is similar to body weight with PD/PK differences because the physiology is different in certain people that are of lower, or higher weight, or larger or smaller size.

Age

• Liver and renal function, skin thickness.
• Can contribute to drug-drug interactions due to multiple medications.

Gender

• Hormone levels, size differences.
• Efforts are increasing to study gender differences in drug responses.

Disease State

• Receptor numbers, neuronal populations.

Genetics

• Single-nucleotide polymorphisms in receptors and enzymes.

Pharmacodynamic vs. Pharmacokinetic Influences

• Pharmacodynamic Potential: Has greater potential for variability due to the complexity of signaling pathways.
• Pharmacokinetic Knowledge: More PK-related single-nucleotide polymorphisms are known due to easier measurement of drug metabolite levels.

Measuring Response in Patients

• Quantal Dose-Response Curve: Number of people responding to a drug at each dose (yes/no response).
• Threshold: A set level to determine if a patient is responding.
• Gaussian Distribution: Most people respond at a certain concentration, with some more and less sensitive.
• Dose-Response Curve: Accumulation of responses at each concentration.

ED50 Threshold

• ED50 (Effective Dose 50%): Dose at which 50% of the population experiences a therapeutic effect.
• TD50 (Toxic Dose 50%): Dose at which 50% of the population experiences toxicity.
• LD50 (Lethal Dose 50%): Dose at which 50% of the population experiences death (primarily used in preclinical studies).

Therapeutic Index and Certain Safety Factor

• Therapeutic Index: Ratio of TD50 to ED50.
• A high therapeutic index is desirable.
• Certain Safety Factor: Ratio of the toxic dose in 1% of the population to the effective dose in 99% of the population.
• It is more indicative of drug safety.

Therapeutic Index Calculation

• Importance of Certain Safety Factor for drugs that do not follow the Law of Mass Action.
• Therapeutic Index Limitations: May not provide complete information if the drug response does not follow the law of mass action.

Risk-to-Benefit Analysis

• Side Effects: Consider the severity and prevalence of side effects relative to the condition being treated.
• Safe Drug Considerations: How rare the therapeutic effects are, and the severity of side effects.

Pharmacist Role

• Minimizing Bad Effects: Minimize the risk of drug-drug interactions.
• Magnifying Good Effects: What other factors can control to minimize bad effects and magnify the good effects for certain indications?

PK-PD Simulations

• Key Concepts Introduced: Stimulus response, dose response curves, pharmacokinetic parameters, pharmacodynamic parameters, single nucleotide polymorphism, and patient variability.
• Simulations relate kinetic receptor kinetics with pharmacokinetic parameters.
• Pharmacokinetic Side: Absorption and elimination of a ligand.
• Pharmacodynamic Side: Ligand concentration, ligand affinity, ligand association constant, and ligand dissociation.

Receptor Kinetics

• Reversible Dynamics: Drugs bind to receptors and can come off; this can be a slow or fast process.
• Binding Kinetics: Parameters are calculated to determine how long a compound will act.
• Duration of Action: Related to the magnitude of occupancy at a target.

Drug-Receptor Function

• Response Mechanism: The response is based on how much drug occupies the receptor.
• Receptor Occupancy: How much drug is binding.
• Intrinsic Efficacy: The amount of drug produces a maximal response.
• Number of Receptors: The quantity of receptors available affects the magnitude of the response.
• Dose-Response Curve and Binding Curve: Linked.

Examples of Simulations

• Potent Ligand with Rapid Kinetics: Ligand concentration reaches a peak and decreases over time.
• Target occupancy: Maximum of about 80% and decreases over time.
• High-Potency Ligand with Slower Receptor Kinetics: Binds and comes off more slowly, resulting in more activity over time.
• Binding becomes the rate-limiting factor.
• High Potency Ligand with Slow Receptor Kinetics (Extended Dissociation): Can cause longer duration of action, but also means a lower peak.
• High Potency Ligand with Slow Dissociation and Faster Elimination: Even though the drug slowly dissociates and hangs onto the receptor, it eliminates faster once it comes off.
• Weak Ligand with Rapid Receptor Kinetics: Less of the drug binds to the target.
• Structure-Activity Relationship (SAR) Studies: Help in designing more potent and selective drugs.

Importance of Time in Drug Action

• Considering the element of time is important when determining the duration of action of a drug and selecting the best drug for a patient.
• Factors include potential side effects, drug-drug interactions, and the desired duration of action

Summary of Key Parameters and Their Effects

• Ligand Concentration: Higher concentration leads to higher initial receptor occupancy.
• Receptor Kinetics (On/Off Rate): Rapid kinetics cause a shorter duration of action, while slow kinetics cause a longer duration of action.
• Ligand Elimination Rate: Faster elimination reduces the amount of drug available to bind, lowering receptor occupancy.
• Ligand Potency: Weaker ligands require higher doses to achieve the same receptor occupancy.
• Patient Variability: Patient's genetic makeup, age, and weight all contribute to the variation in drug response.

Explore key concepts in ligand-receptor interactions. Understand drug development stages, receptor binding effects, and the significance of receptor structures. Learn about ligand properties and implications of receptor variability.