1.1 Receptor theory

Receptor theory forms the foundation of drug action, explaining how drugs interact with specific targets in the body. This topic delves into the intricacies of receptor-ligand interactions, exploring concepts like binding affinity, efficacy, and the differences between agonists and antagonists.

Understanding receptor activation mechanisms and classification is crucial for drug development. The notes cover various receptor types, including GPCRs and ion channels, and explore quantitative aspects of receptor pharmacology, such as dose-response relationships and EC50 values.

Receptor-ligand interactions

• Receptor-ligand interactions form the basis of drug action, where drugs (ligands) bind to specific receptors to elicit a pharmacological response
• Binding of a ligand to a receptor depends on factors such as shape complementarity, electrostatic interactions, and hydrogen bonding
• Receptor-ligand interactions can be characterized by binding affinity (strength of the interaction) and efficacy (ability to produce a biological effect)

Binding affinity vs efficacy

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• Binding affinity refers to the strength of the interaction between a ligand and its receptor, typically expressed as the dissociation constant (Kd)
  • Ligands with higher affinity bind more tightly to the receptor and have lower Kd values
  • Affinity is determined by the rate of association (kon) and dissociation (koff) of the ligand-receptor complex
• Efficacy describes the ability of a ligand to produce a biological response upon binding to the receptor
  • Ligands with high efficacy (full agonists) elicit a maximal response, while those with lower efficacy (partial agonists) produce a submaximal response
  • Efficacy is influenced by factors such as receptor density, coupling efficiency, and tissue-specific factors

Agonists vs antagonists

• Agonists are ligands that activate receptors upon binding, leading to a biological response
  • Full agonists produce a maximal response, while partial agonists elicit a submaximal response compared to full agonists
  • Examples of agonists include endogenous neurotransmitters (acetylcholine) and hormones (insulin)
• Antagonists are ligands that bind to receptors but do not activate them, thereby blocking the action of agonists
  • Competitive antagonists compete with agonists for the same binding site, and their effects can be overcome by increasing agonist concentration
  • Non-competitive antagonists bind to a different site on the receptor and cannot be overcome by increasing agonist concentration
  • Examples of antagonists include beta-blockers (propranolol) and antihistamines (cetirizine)

Orthosteric vs allosteric binding

• Orthosteric binding refers to the interaction of a ligand with the primary (active) site on the receptor, where endogenous ligands typically bind
  • Orthosteric ligands compete directly with endogenous ligands and can be agonists or antagonists
  • Examples of orthosteric ligands include morphine (mu-opioid receptor agonist) and flumazenil (benzodiazepine receptor antagonist)
• Allosteric binding involves the interaction of a ligand with a site distinct from the orthosteric site, known as an allosteric site
  • Allosteric modulators can enhance (positive allosteric modulators) or reduce (negative allosteric modulators) the response to orthosteric ligands
  • Allosteric modulators offer the advantage of greater receptor subtype selectivity and may have a lower risk of side effects compared to orthosteric ligands
  • Examples of allosteric modulators include benzodiazepines (GABAA receptor positive allosteric modulators) and cinacalcet (calcium-sensing receptor positive allosteric modulator)

Saturation binding curves

• Saturation binding curves describe the relationship between ligand concentration and receptor occupancy at equilibrium
  • As ligand concentration increases, receptor occupancy increases until a plateau is reached, indicating that all receptors are occupied
  • Saturation binding curves can be used to determine the dissociation constant (Kd) and the maximum number of binding sites (Bmax)
• Scatchard plots, derived from saturation binding curves, provide a linear representation of the data and can be used to identify receptor subtypes or cooperative interactions
  • In a Scatchard plot, the ratio of bound to free ligand (B/F) is plotted against the concentration of bound ligand (B)
  • A single straight line indicates a single population of receptors, while deviations from linearity suggest multiple receptor subtypes or cooperative interactions

Receptor activation mechanisms

• Receptor activation involves the transduction of a ligand binding event into a cellular response
• Different receptor classes employ various mechanisms to transduce the signal, including conformational changes, second messenger signaling, ion channel opening/closing, and receptor dimerization
• Understanding receptor activation mechanisms is crucial for designing drugs that can modulate receptor function and elicit desired pharmacological effects

Conformational changes

• Ligand binding can induce conformational changes in the receptor, leading to the exposure of previously hidden sites or the stabilization of active receptor states
  • Conformational changes may involve rearrangements of transmembrane helices, loops, or domains
  • These changes can facilitate the binding of intracellular signaling proteins or alter the receptor's interaction with other cellular components
• Examples of receptors that undergo conformational changes upon activation include G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs)
  • In GPCRs, agonist binding promotes a conformational change that allows the receptor to interact with and activate G proteins
  • In LGICs, ligand binding induces a conformational change that opens the associated ion channel, allowing the flow of ions across the membrane

Second messenger signaling

• Many receptors, particularly GPCRs, transduce signals through the activation of second messenger systems
  • Second messengers are small, diffusible molecules that amplify and relay the signal from the receptor to downstream effectors
  • Common second messengers include cyclic AMP (cAMP), cyclic GMP (cGMP), calcium (Ca2+), and inositol trisphosphate (IP3)
• Activation of second messenger systems can lead to the modulation of various cellular processes, such as enzyme activity, gene transcription, and ion channel function
  • For example, activation of the beta-adrenergic receptor leads to an increase in cAMP levels, which activates protein kinase A (PKA) and results in the phosphorylation of downstream targets
  • Activation of the muscarinic acetylcholine receptor can lead to an increase in IP3 and diacylglycerol (DAG) levels, which promote calcium release from intracellular stores and activate protein kinase C (PKC), respectively

Ion channel opening/closing

• Ligand-gated ion channels (LGICs) are receptors that contain an integral ion channel, which opens or closes in response to ligand binding
  • Opening of the ion channel allows the flow of specific ions (e.g., Na+, K+, Ca2+, Cl-) across the membrane, leading to changes in the cell's electrical excitability or intracellular ion concentrations
  • Closing of the ion channel stops the flow of ions and returns the cell to its resting state
• Examples of LGICs include nicotinic acetylcholine receptors (nAChRs), GABAA receptors, and glutamate receptors (AMPA, NMDA, and kainate receptors)
  • Activation of nAChRs by acetylcholine leads to the opening of the associated cation channel, causing depolarization of the cell membrane
  • Activation of GABAA receptors by GABA leads to the opening of the associated chloride channel, causing hyperpolarization of the cell membrane and reducing neuronal excitability

Receptor dimerization

• Some receptors, such as receptor tyrosine kinases (RTKs) and certain GPCRs, require dimerization for activation and signal transduction
  • Dimerization involves the physical association of two receptor monomers, which can be homodimers (identical subunits) or heterodimers (different subunits)
  • Ligand binding can promote or stabilize receptor dimerization, leading to the activation of the receptor's intracellular signaling domains
• Dimerization allows for the trans-phosphorylation of the receptor's intracellular domains, creating docking sites for downstream signaling proteins
  • For example, binding of growth factors (e.g., EGF, PDGF) to their respective RTKs promotes receptor dimerization and trans-phosphorylation, leading to the activation of signaling cascades such as the MAPK and PI3K pathways
  • Some GPCRs, such as the GABAB receptor and the metabotropic glutamate receptors (mGluRs), require dimerization for efficient coupling to G proteins and subsequent signal transduction

Receptor classification

• Receptors can be classified based on their structure, function, or the type of ligand they bind
• Understanding the different classes of receptors is essential for developing targeted therapies and predicting drug-receptor interactions
• The main classes of receptors include G protein-coupled receptors (GPCRs), ligand-gated ion channels (LGICs), receptor tyrosine kinases (RTKs), and nuclear receptors

G protein-coupled receptors (GPCRs)

• GPCRs are the largest family of cell surface receptors and are targeted by approximately 30% of currently marketed drugs
  • GPCRs have a characteristic structure consisting of seven transmembrane helices, an extracellular N-terminus, and an intracellular C-terminus
  • Ligand binding to the extracellular domain or transmembrane pocket induces a conformational change that allows the receptor to couple to and activate G proteins
• GPCRs transduce signals through the activation of heterotrimeric G proteins, which modulate the activity of effector proteins such as enzymes and ion channels
  • G proteins are classified into four main families: Gs (stimulates adenylyl cyclase), Gi (inhibits adenylyl cyclase), Gq (activates phospholipase C), and G12/13 (regulates Rho GTPases)
  • The specific G protein coupled to a GPCR determines the downstream signaling pathway and cellular response
• Examples of GPCRs include adrenergic receptors, dopamine receptors, serotonin receptors, and opioid receptors

Ligand-gated ion channels

• Ligand-gated ion channels (LGICs) are receptors that contain an integral ion channel, which opens or closes in response to ligand binding
  • LGICs are typically composed of multiple subunits that assemble to form a central pore, which serves as the ion channel
  • Ligand binding to the extracellular domain induces a conformational change that opens the ion channel, allowing the flow of specific ions across the membrane
• LGICs are classified based on the type of ion they conduct (e.g., cation-selective or anion-selective) and the ligand they respond to
  • Cation-selective LGICs include nicotinic acetylcholine receptors (nAChRs), serotonin 5-HT3 receptors, and ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors)
  • Anion-selective LGICs include GABAA receptors and glycine receptors
• LGICs play a crucial role in fast synaptic transmission and are targeted by drugs such as benzodiazepines (GABAA receptor modulators) and general anesthetics

Receptor tyrosine kinases

• Receptor tyrosine kinases (RTKs) are cell surface receptors that possess intrinsic tyrosine kinase activity in their intracellular domains
  • RTKs have an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular tyrosine kinase domain
  • Ligand binding to the extracellular domain promotes receptor dimerization and trans-phosphorylation of the intracellular tyrosine residues
• Phosphorylated tyrosine residues serve as docking sites for downstream signaling proteins containing SH2 or PTB domains, leading to the activation of signaling cascades
  • Key signaling pathways activated by RTKs include the MAPK pathway, PI3K/Akt pathway, and PLCγ/PKC pathway
  • These pathways regulate cellular processes such as proliferation, differentiation, survival, and metabolism
• Examples of RTKs include the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and insulin receptor
• RTKs are important targets for cancer therapy, with drugs such as monoclonal antibodies (e.g., trastuzumab) and small-molecule tyrosine kinase inhibitors (e.g., imatinib) being used to inhibit aberrant RTK signaling in various malignancies

Nuclear receptors

• Nuclear receptors are intracellular receptors that function as ligand-activated transcription factors
  • Nuclear receptors have a modular structure consisting of a variable N-terminal domain, a central DNA-binding domain, and a C-terminal ligand-binding domain
  • Ligand binding to the ligand-binding domain induces a conformational change that allows the receptor to interact with specific DNA sequences (response elements) and regulate gene transcription
• Nuclear receptors can be classified into four main classes based on their ligand-binding and dimerization properties
  • Steroid hormone receptors (e.g., estrogen receptor, glucocorticoid receptor) bind to DNA as homodimers and are activated by lipophilic hormones that diffuse across the cell membrane
  • Thyroid hormone receptors, vitamin D receptor, and retinoic acid receptors form heterodimers with the retinoid X receptor (RXR) and are activated by their respective lipophilic ligands
  • Orphan receptors (e.g., peroxisome proliferator-activated receptors, liver X receptors) form heterodimers with RXR and are activated by metabolic intermediates or synthetic ligands
  • Monomeric orphan receptors (e.g., steroidogenic factor-1, nuclear receptor subfamily 4 group A members) bind to DNA as monomers and are often constitutively active or regulated by post-translational modifications
• Nuclear receptors play essential roles in regulating development, metabolism, and homeostasis, and are important targets for drugs such as tamoxifen (estrogen receptor modulator) and thiazolidinediones (peroxisome proliferator-activated receptor gamma agonists)

Quantitative receptor pharmacology

• Quantitative receptor pharmacology involves the mathematical analysis of drug-receptor interactions and the resulting pharmacological effects
• Key concepts in quantitative receptor pharmacology include dose-response relationships, EC50 and IC50 values, receptor reserve, and the distinction between efficacy and potency
• Understanding these concepts is essential for the design and optimization of drugs targeting specific receptors

Dose-response relationships

• Dose-response relationships describe the relationship between drug concentration (or dose) and the observed pharmacological effect
  • Dose-response curves are typically sigmoidal in shape, with the effect increasing as the drug concentration increases until a maximum effect is reached
  • The steepness of the dose-response curve is determined by the Hill coefficient, which reflects the degree of cooperativity in the drug-receptor interaction
• Dose-response relationships can be used to compare the potency and efficacy of different drugs acting on the same receptor
  • Parallel shifts in the dose-response curve indicate changes in potency, while changes in the maximum effect indicate changes in efficacy
  • Competitive antagonists cause a rightward shift in the dose-response curve without affecting the maximum effect, while non-competitive antagonists reduce the maximum effect without shifting the curve

EC50 and IC50 values

• The EC50 (half-maximal effective concentration) is the concentration of a drug that produces 50% of its maximum effect
  • EC50 values are used to compare the potency of drugs acting as agonists or partial agonists
  • Lower EC50 values indicate higher potency, as less drug is required to produce a given effect
• The IC50 (half-maximal inhibitory concentration) is the concentration of a drug that inhibits a biological process by 50%
  • IC50 values are used to compare the potency of drugs acting as antagonists or inhibitors
  • Lower IC50 values indicate higher potency, as less drug is required to inhibit the biological process
• EC50 and IC50 values can be determined from dose-response curves and are useful for comparing the potency of drugs within the same class or targeting the same receptor

Receptor reserve and spare receptors

• Receptor reserve (or spare receptors) refers to the phenomenon where the maximum response can be achieved by occupying only a fraction of the available receptors
  • In the presence of receptor reserve, the dose-response curve shifts to the left, as less drug is required to produce a given effect
  • Receptor reserve can be quantified using the method of partial irreversible receptor inactivation, which compares the EC50 values before and after reducing the number of available receptors
• The concept of receptor reserve has important implications for drug dosing and the therapeutic window
  • Drugs acting on receptors with a large receptor reserve may have a wider therapeutic window, as a larger change in receptor occupancy is required to produce a significant change in the pharmacological effect
  • Conversely, drugs acting on receptors with little or no receptor reserve may have a narrower therapeutic window and require more precise dosing

Efficacy vs potency

• Efficacy refers to the maximum effect that a drug can produce, regardless of the concentration
  • Full agonists have high efficacy and can produce the maximum possible response, while partial agonists have lower efficacy and produce a submaximal response
  • Effic