Untitled Quiz

Receptor Pharmacology

• Receptor pharmacology is the study of interactions between receptors and drugs/chemicals foreign to the body.
• Most drugs target receptors through receptor interactions.
• Understanding receptor pharmacology is essential in understanding drug effects, mechanisms of action, and their properties.

Introduction to Receptor Pharmacology

• This is a foundational area in the field.
• A lecture's topic.

Ligand-receptor interactions and Dose Response Relationships

• Ligands interact with specific receptors.
• Dose-response relationships elucidate how drug concentration or dose influences the response.

Agonist, antagonist and Inverse Agonist

• Agonist: binds to and activates a receptor.
• Antagonist: binds to a receptor without activating it, thus blocking agonist action
• Inverse agonist: binds to and inhibits a receptor.

Cooperativity, allosteric interactions

• These concepts describe how drug action can be modulated by modifying interaction sites.
• Allosteric interactions involve alteration of a molecule's conformation through non-covalent interaction.

Who is Dr. Ly Vu

• Ly Phuong Vu (or Vu Phuong Ly), originally from Hanoi, Vietnam.
• Holds a BSc in Molecular Biology from Vietnam National University, Hanoi.
• Earned a PhD in Cancer Biology from Memorial Sloan Kettering Cancer Center, NY.
• Performed postdoctoral work in Molecular Pharmacology and Cancer Biology at Memorial Sloan Kettering Cancer Center, NY.
• Joined the Terry Fox Laboratory, BC Cancer in July 2019.
• Joined the Faculty of Pharmaceutical Sciences at UBC in January 2022.
• Teaches PHRM-100 (this lecture) as well as PHRM 333 - Pharmacotherapy in Oncology.

Learning Objectives

• Define different types of receptors and ligands.
• Describe the history of Receptor Theory.
• Identify examples of ligands and drugs acting on various receptors.

Definition of Receptors

• Receptors are cellular components interacting with specific ligands (e.g. drugs) triggering subsequent effects.
• Usually membrane-bound or intracellular proteins.
• Macromolecules such as proteins, DNA, and RNA can be receptors.

Why cells need Receptors?

• Receptors enable cells to interact with their environment (neural, other cells in tissues, and the immune system)
• Receptors serve as a means of communication.
• They are essential for proper cell function, homeostasis, and overall body regulation.

Mode of delivering signals to receptors

• Five methods exist to transmit signals to receptors including:
  • Paracrine signaling
  • Endocrine signaling
  • Autocrine signaling
  • Neurotransmitter signaling
  • Cell-cell interaction

Definition of Ligands

• Ligands are molecules binding to a receptor.
• They trigger cellular behavior or structure alteration.
• Categorized based on location (intracellular or extracellular)

Types of Ligands

• Classified by chemical properties (water-soluble or lipid-soluble)
• Classified by nature (gases, cholesterol, amino acids, peptides, proteins, nucleotides)

Types of Receptors

• Classified based on location (cell surface or intracellular).
• Cell surface: typically trigger downstream cell signaling pathways.
• Intracellular: typically directly trigger downstream transcriptional activities of gene activation/inhibition.
• Three types of cell-surface receptors: G protein-coupled receptors, enzyme-linked receptors, and ion channel receptors

Cell surface receptors

• Are transmembrane proteins in the plasma membrane.
• Have extracellular components for ligand binding and intracellular components for signal transduction.
• Three main types, sharing structural and functional similarities.

G protein-coupled receptors

• Single polypeptide with seven transmembrane domains and intervening parts.
• Interact with G proteins in the plasma membrane.
• Conformational change in the GPCR triggers G protein activation.
• G proteins bind guanine nucleotides (GTP/GDP) that control activity.

Enzyme-linked receptors

• Usually have only one transmembrane domain and a cytosolic domain (either intrinsic enzyme activity or associated with one).
• Responses to signals are relatively slow (minutes to hours) and involve many intracellular signaling steps that eventually alter gene expression.
• Example includes receptors for growth, proliferation, differentiation, survival of cells.

Ion channel receptors

• Multimeric proteins in the plasma membrane forming an opening (pore) across the membrane.
• Open/close in response to chemical or mechanical signals.
• Extremely fast responses (milliseconds).
• Individual ion channels are specific to particular ions.
• Nicotinic receptors for neurotransmitters example.

Intracellular receptors

• Typically globular proteins located in the cytoplasm or nucleus.
• Bind lipid-soluble chemical messengers (steroids, hormones, retinoic acid, vitamin D etc.)
• Once activated, they induce gene expression changes by binding to "response elements" on DNA.
• Effects are slow (minutes to hours), lasting longer due to protein/enzyme activity.

Drugs as ligands for receptors to elicit responses

• Different drug groups can act as ligands for different types of receptors.
• This table provides examples of some major classes of drugs interacting with corresponding receptors.
  • Receptors are categorized into G Protein-coupled receptors, Enzyme-linked receptors, ion channel receptors, and intracellular receptors.
  • Drug Groups are categorized as Adrenergic receptor agonists/antagonists, Insulin and estrogen/progesterone agonists, Neuronal receptor modulators, and Steroid drugs.

The importance of Receptor Theory/Concept

• The receptor concept is fundamental to understanding drug action in relation to homeostasis and physiology.
• Receptors form the basis for quantifying relationships between doses of drugs and their effects.
• They are responsible for drug selectivity and mediate the actions of various agents.

Introduction of Receptor Concept

• Early researchers proposed the idea of a 'receptive substance' in cells for compounds (compounds similar to what happens when 2 inorganic chemicals combine).
• Langley's and Ehrlich's work in the late 19th / early 20th centuries formed the foundation for the receptor theory.
• Ehrlich proposed 'Side Chain Theory of Immunity' describing how toxins bind to cells through specific sites or chains.
• Ehrlich formulated the "magic-bullet" concept of drugs interacting with specific cell targets.
• These early observations contributed significantly to the receptor concept.

History of Receptor Theory/Concept

• Various researchers contributed to the development of the receptor theory.
• These individuals suggested ways to classify receptors of cells.
• Dates of key contributions provide a chronological understanding of how the receptor theory evolved.

Ligand/drug-receptor interactions and Dose Response Relationships

• Focuses on the interaction between ligands and receptors during drug actions and quantifiable responses.

Learning Objectives

• Understand and describe drug-receptor interactions.
• Outline techniques to measure ligand-receptor interactions.
• Define, describe and understand dose-response relationships including their implications.
• Define drug specificity and selectivity, including the basis and use of dose-response curves.
• Define terms like ED50, TD50, and therapeutic index.
• Explain factors influencing dose-response curves.

Recognition of the ligand at receptor site

• The lock-and-key model illustrates how ligands and receptors perfectly match.
• The induced fit model expands on this, suggesting the receptor's shape changes upon ligand binding.

Drug-Receptor binding forces

• Four key types of binding include hydrophobic bonds, hydrogen bonds, ionic bonds, and covalent bonds.
• Strength of binding influences the duration of drug-receptor engagement (seconds to hours).

Drug specificity vs. selectivity

• Drug selectivity is how a drug preferentially targets its intended receptor over other receptors.
• Drug specificity further describes how a drug produces only the intended effect without others.
• Factors influencing specificity/selectivity include ligand affinity, interaction sites, and receptor presence in various tissues.

Measuring ligand-receptor interaction

• Ligand-binding assays measure initial ligand-receptor interaction.
• Functional assays measure the biological consequence of ligand-receptor interaction.

Dose-Response Relationship

• The relationship between administered dose and the resulting effect or response.
• Dose-response curves are not linear; rather affected by minimum threshold and upper limits or ceiling effects.

Occupancy Theory/Occupation Concept

• Explains how the degree of receptor activation depends on the interaction between the drug and its receptor and the concentration or dose.
• Quantifiable dose-response curves, and how different drugs exhibit different potencies in producing a specific response.

What is dose response curve?

• Graphically representing the relationship between drug dose (or concentration) and its response.
• Two elements are required to construct a dose response curve- drug doses and percentage response for each dose.

Fractional occupancy

• Mathematical model determining the portion of receptors bound to a ligand at equilibrium.

Utility of the [log] dose response curve

• Allows visualization of a wide concentration range.
• Convenient for comparing responses to different drugs.

Graded dose response curve

• The magnitude of the biological response is proportional to the administered drug's dose.
• Increasing doses progressively activate more receptors on the cell/tissue, reaching maximal response when all the receptors are occupied.

Understanding Dose response curve

• Key characteristics derived from a graded dose-response curve include potency and efficacy, and their measurement.
• Characteristics include slope and variability associated with a drug's response.

Drug Potency and Efficacy

• Potency refers to the drug concentration required for a 50% response effect.
• Efficacy is the maximum response effect a drug can achieve.

Slope and Variability

• Slope relates to the effect of escalating drug doses.
• Variability refers to the dispersion or consistency of responses.

Reading the curves

• Interpretation of dose-response curves to determine potency and efficacy values of drugs.
• Factors that influence these parameters.

Modifications of the Occupancy Theory

• Ariens’ and Stephenson’s modifications of Clark's Occupancy theory introduce new factors such as intrinsic efficacy (a parameter influencing response even at low occupancy).

Quantal dose response curve

• Illustrates the relationship between drug concentration and the percentage of a population exhibiting a defined effect.
• Useful for analyzing the response in different subjects to varied drug doses.
• Describes varied results obtained in different members of a population when the desired amount of a dose is administered.

ED50 and LD50

• ED50 is the dose needed to elicit an effect in 50% of subjects.
• LD50 is the dose which kills 50% of study subjects.

TD50 and Therapeutic index

• TD50: Dose at which 50% of subjects experience a toxic effect.
• Therapeutic index assesses drug selectivity, showing the ratio of TD50 (toxic dose) to ED50 (effective dose), indicating how selective the drug is for its intended effect over harmful side effects.

Implications and Caveats of Therapeutic index

• Importance of therapeutic level monitoring for drugs with a narrow therapeutic index.
• Narrow therapeutic index drugs require more frequent and precisely measured dosing.
• Difficulties in determining a precise LD50 or TD50 may cause issues, and the misinterpretation of risk for drugs with a narrow therapeutic index can be observed.

Therapeutic range/window

• The range of doses producing a therapeutic effect without causing significant toxicity.