3.2 Mechanisms of drug action and receptor binding

Drug action and receptor binding are crucial to understanding how medications work in the body. This topic explores how drugs interact with specific proteins called receptors, triggering biological responses. It delves into the mechanics of binding, factors that influence it, and various types of drug-receptor interactions.

Receptor modulation and signal transduction pathways are key concepts in this section. We'll learn about allosteric modulation, which fine-tunes receptor responses, and how signals are converted into cellular actions. This knowledge is essential for grasping how drugs affect our bodies at a molecular level.

Receptor Binding

Key Concepts in Receptor Binding

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• Receptors function as specialized proteins located on cell surfaces or within cells that recognize and bind specific molecules
• Agonists activate receptors by binding and triggering a biological response, mimicking the action of endogenous ligands
• Antagonists bind to receptors without activating them, blocking the action of agonists and preventing biological responses
• Affinity describes the strength of binding between a drug and its receptor, measured by the concentration required for occupation
• Efficacy refers to the maximum response a drug can produce when bound to its receptor, regardless of dose

Receptor Binding Dynamics

• Receptor binding involves a lock-and-key mechanism where drugs fit into specific binding sites
• Binding can occur reversibly or irreversibly, affecting the duration of drug action
• Competitive binding happens when multiple drugs compete for the same receptor site
• Non-competitive binding occurs when drugs bind to different sites on the receptor
• Receptor saturation occurs when all available binding sites are occupied, leading to a plateau in drug effect

Factors Influencing Receptor Binding

• Chemical structure of the drug determines its ability to bind to specific receptors
• Concentration gradient affects the rate of drug binding, with higher concentrations leading to faster binding
• Temperature influences binding kinetics, with higher temperatures generally increasing binding rates
• pH can alter the ionization state of drugs and receptors, affecting binding affinity
• Presence of other molecules can interfere with or enhance binding through various mechanisms (allosteric modulation)

Receptor Modulation

Allosteric Modulation and Its Effects

• Allosteric modulation involves binding to a site distinct from the primary binding site
• Positive allosteric modulators enhance receptor function by increasing binding affinity or efficacy
• Negative allosteric modulators decrease receptor function by reducing binding affinity or efficacy
• Allosteric modulators can fine-tune receptor responses without directly activating or blocking the receptor
• Examples of allosteric modulators include benzodiazepines (GABA receptors) and maraviroc (CCR5 receptors)

Signal Transduction Pathways

• Signal transduction converts extracellular signals into intracellular responses
• Includes cascades of biochemical reactions triggered by receptor activation
• Second messengers (cAMP, IP3, DAG) amplify and propagate signals within cells
• Protein kinases phosphorylate target proteins, altering their activity and cellular functions
• Transcription factors regulate gene expression in response to receptor activation
• Signal termination mechanisms prevent prolonged or excessive cellular responses

G-Protein Coupled Receptors (GPCRs)

• GPCRs constitute the largest family of membrane receptors in eukaryotes
• Consist of seven transmembrane domains with extracellular and intracellular loops
• Activation leads to conformational changes, triggering G-protein dissociation and activation
• G-proteins (Gs, Gi, Gq) modulate various effector proteins and second messenger systems
• GPCR signaling regulates diverse physiological processes (neurotransmission, hormone action, sensory perception)
• Desensitization and internalization mechanisms regulate GPCR responsiveness

Drug Targets

Ion Channels as Drug Targets

• Ion channels control the flow of ions across cell membranes, regulating cellular excitability
• Voltage-gated channels respond to changes in membrane potential (sodium, potassium, calcium channels)
• Ligand-gated channels open in response to specific molecules (nicotinic acetylcholine receptors, GABA receptors)
• Drugs can modulate ion channels by blocking pores, altering gating kinetics, or influencing channel conductance
• Ion channel modulators treat various conditions (local anesthetics, antiepileptics, antiarrhythmics)

Enzyme Inhibition Mechanisms

• Enzyme inhibitors interfere with catalytic activity by binding to active or allosteric sites
• Competitive inhibitors compete with substrates for the active site, reversible with increased substrate concentration
• Non-competitive inhibitors bind to allosteric sites, reducing enzyme activity regardless of substrate concentration
• Irreversible inhibitors form covalent bonds with enzymes, permanently inactivating them
• Enzyme inhibition targets include neurotransmitter metabolism, protein synthesis, and cellular signaling pathways
• Examples of enzyme inhibitors include statins (HMG-CoA reductase), proton pump inhibitors, and ACE inhibitors