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Questions and Answers
What happens to G alpha upon receptor stimulation by an agonist?
What happens to G alpha upon receptor stimulation by an agonist?
What is a characteristic of G protein-coupled receptors (GPCRs)?
What is a characteristic of G protein-coupled receptors (GPCRs)?
Which of the following statements about G proteins is true?
Which of the following statements about G proteins is true?
What role does adenylyl cyclase play in G protein signaling?
What role does adenylyl cyclase play in G protein signaling?
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Which of the following ligands can act on both ionotropic receptors and G protein-coupled receptors?
Which of the following ligands can act on both ionotropic receptors and G protein-coupled receptors?
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What defines the pharmacodynamics of a drug?
What defines the pharmacodynamics of a drug?
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Which statement about ion channels and drug action is true?
Which statement about ion channels and drug action is true?
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What is the primary function of the GABAA receptor when GABA binds to its sites?
What is the primary function of the GABAA receptor when GABA binds to its sites?
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How many predicted drug targets are encoded by the human genome according to the content?
How many predicted drug targets are encoded by the human genome according to the content?
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Which of the following receptor classes is correctly matched with its characteristic?
Which of the following receptor classes is correctly matched with its characteristic?
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Study Notes
Pharmacodynamics
- Pharmacodynamics is the action of a drug on the body.
- It describes the relationship between drug concentrations and responses.
- Most drugs initially bind to target proteins called receptors on or within cells.
- Some drug targets are non-protein, such as ions, lipids, DNA, or water.
- Drugs binding to receptors manipulate or "hijack" the function of endogenous ligands, thereby directing biological processes.
The Druggable Genome
- The "druggable genome" refers to subsets of genes expressing proteins capable of binding to drug-like molecules.
- Hopkins and Groom (2002) detailed the distribution of targets for current drugs.
- Approximately 3,000 of the predicted 30,000 genes in the human genome encode a "druggable" protein.
- Key protein families that represent drug targets include, but are not limited to; G protein-coupled receptors (GPCRs), protein kinases, and ion channels.
Receptor Classes
- Ion channels: Fast acting, controlling ion flow through plasma membranes. Examples: GABA, glycine, nicotinic acetylcholine, glutamate.
- G protein-coupled receptors (GPCRs): Moderate speed, initiating a signaling cascade through G-proteins. Examples: GABA, acetylcholine.
- Receptor Tyrosine Kinases (RTKs): Slower, involve phosphorylation. Duration is minutes to hours.
- Steroid receptor superfamily: Slowest, involve DNA interactions. Duration is hours to days.
- Other receptor classes exist
Drug-Receptor Binding
- Irreversible covalent binding: A shared electron pair, often creating a lasting impact after drug removal. Example: Aspirin's acetylation of cyclooxygenase.
- Reversible binding: Typical of G protein-coupled receptors.
Dose-Response Curves
- Dose-response curves illustrate the relationship between drug dosage and the magnitude of the response.
- Different drugs may exhibit different potencies as defined by ED50 values.
Studying Drug-Receptor Binding
- Methods include radioligand binding assays, where radioactive ligands are used to measure binding, and fluorescent ligand binding assays; these include FRET (Fluorescence Resonance Energy Transfer) and BRET (Bioluminescence Resonance Energy Transfer) assays for more detailed study of receptor activity.
Radioligand Binding Assay
- Requires radioactive ligand to detect ligand–receptor interactions in tissue.
- Specificity is crucial for accurate results; the ligand should strongly bind to the specific receptor and not other sites.
- Affinity is important to ensure rapid and efficient binding to the target receptor
Radioligand Binding Assay - "Saturation Binding"
- Receptors can be saturated at higher concentrations
- Bmax – maximum number of receptors that can be occupied
- KD - Dissociation constant, half-maximal drug concentration, indicates the affinity to receptors.
KD Dissociation Constant
- KD is the equilibrium dissociation constant, showing the affinity of the ligand to the target receptor.
- It is the concentration of ligand where half of the receptors are bound.
- The mass action equation describes the interactions among receptors, drug, and complex.
Scatchard Plots
- A graphical representation to analyze receptor binding data (with non-linear curves).
- Provides a graphical way to determine the maximum number of binding sites per protein (Bmax) and the dissociation constant (Kd).
Comparing Drug Potency
- Potency refers to the amount of drug needed to elicit a specific response or fraction of binding to a receptor.
- Analyzing Semi-log Dose-response curves and ED50 (dose that elicits 50% of maximal response) values allow for comparison of drugs.
Comparing Drug Efficacy
- Efficacy describes the inherent ability of a drug to induce a maximal response after binding to the receptor.
- A higher maximal response indicates higher efficacy.
Agonist vs antagonist
- Agonists bind to receptors and activate them, usually mimicking naturally-occurring ligands.
- Antagonists bind to receptors but do not activate them.
- They block the binding of agonists or prevent activation.
- Competitive antagonists compete with agonists for binding sites.
- Non-competitive antagonists bind to different sites on the receptor.
Types of Agonists
- Full agonists: produce full response at maximal receptor occupancy.
- Partial agonists: produce less than a full response at maximal receptor occupancy; can act as antagonists in the presence of a full agonist.
- Inverse agonists: bind to and activate the receptor's inactive state.
Biased Agonism
- Biased agonists activate particular subsets of downstream signaling pathways via receptors, rather than inducing a general response.
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Description
Explore the fundamental concepts of pharmacodynamics, including drug action on the body and the interaction with receptors. Learn about the druggable genome and the significance of various receptor classes in drug targeting. This quiz will enhance your understanding of how drugs manipulate biological processes.
