Receptor Binding and Types Quiz

Receptor Binding

• Receptors can be recycled and new ones are created, leading to no permanent effect.
• An allosteric site is separate from the active binding site but can affect the receptor's function.
• Binding to the allosteric site can be reversible or irreversible.
• Allosteric binding can modify the potency and/or efficacy of agonists.
• Non-receptor antagonists work by inactivating agonists before they bind to the receptor.
• Partial agonists can act as antagonists in the presence of a full agonist.
• Partial agonists compete with full agonists for the same binding site.
• Partial agonists reduce the potency of full agonists without affecting efficacy.
• When the full agonist is absent, partial agonists function as normal agonists.

Receptor Types

• Kinase-linked receptors have enzymatic cytosolic domains, often tyrosines.
• Kinase-linked receptors are usually dimeric peptides, activated by ligand binding.
• Kinase-linked receptors mediate signaling of growth factors, cytokines, and hormones like insulin.
• Nuclear receptors are monomeric proteins that often reside in the nucleus.
• Ligand binding to nuclear receptors alters their conformation, causing them to translocate to the nucleus.
• Nuclear receptors dimerize and bind to DNA in the nucleus, regulating gene expression.
• Ion channels are receptors that allow the passage of specific ions.
• Ligand-gated and voltage-gated channels are distinct receptor subtypes.
• Enzymes, like angiotensin-converting enzyme (ACE), can be targeted for therapeutic purposes.
• Blocking ACE with agents like enalapril can prevent the formation of angiotensin II, which is a vasoconstrictor.
• Transporters also bind to and transport specific ions and small molecules across cell membranes.

The Autonomic Nervous System

• The Autonomic Nervous System (ANS) has broad therapeutic applications but can also cause adverse effects.
• Neurons consist of dendrites, soma, axons, and pre-synaptic terminals.
• Dendrites receive synaptic input, while the soma manages cellular processes.
• Axons conduct action potentials, and pre-synaptic terminals release neurotransmitters.
• The ANS integrates information from internal and external environments.
• Central Nervous System (CNS) processes information and initiates responses to maintain homeostasis.
• The Peripheral Nervous System (PNS) connects the CNS to the body.
• The PNS includes cranial nerves, spinal nerves, peripheral ganglia, and sensory receptors.
• Tissue responses are governed by feedback loops and controlled by the CNS.

What is a Drug?

• A chemical substance with a known structure; not a nutrient or essential dietary ingredient
• When administered to a living organism, it produces a biological effect

Drug Origins

• Aspirin (synthetic)
• Parathyroid hormone (genetically engineered)
• Morphine from opium poppy (phytochemical)
• Anti-inflammatory drug Aspirin was originally found in the animal kingdom
  • It is now manufactured synthetically for time and cost efficiency
• Parathyroid hormone is used to treat hypoparathyroidism
  • Hypoparathyroidism is a lack of parathyroid hormone, which causes hypercalcemia
• Morphine is extracted from the opium poppy to create alkaloids
  • These alkaloids are used to treat opioid addiction and pain

Drug Interactions with Molecular Targets

• Receptors are biological macromolecules that recognize and respond to endogenous chemical signals or exogenous drugs
  • Agonist: A ligand that activates the receptor
  • Antagonist: A ligand that binds to the receptor but does not activate it
• Ligand-gated ion channels are tube-like macromolecules with protein subunits that pass through the plasma membrane
  • Ligands bind to the extracellular or intracellular regions of the channel
  • Binding alters the conductance of ions through the channel
  • Examples: Nicotinic acetylcholine transporter, which opens sodium channels to initiate an action potential
• G-protein coupled receptors: Typically found on the plasma membrane
  • They have 7 transmembrane regions
  • The extracellular region binds to ligands
  • The G-protein (composed of alpha and beta-gamma subunits) are not covalently linked
  • They interact with effectors like enzymes, ion channels, transporters and gene transport regulators
  • Examples: Muscarinic acetylcholine receptors
• Kinase-linked receptors: Transmembrane receptors with enzymatic cytosolic domains
  • Tyrosine kinase is the largest of these receptors
  • Usually large dimeric peptides
  • They are targeted for growth factors, cytokines and hormones
  • Activation occurs upon ligand binding, leading to dimerization and transphosphorylation of tyrosine residues
  • Examples: Insulin receptors
• Nuclear receptors: Monomeric proteins
  • These are normally expressed in the nucleus, but can also be present in the cytosol
  • Upon ligand binding, the receptors undergo a conformational change and translocate to the nucleus
  • They dimerize and bind to DNA, which alters the transcription rate and modulates protein expression
  • Examples: Steroid hormone receptors

Ion Channels

• Ion channels allow the passage of particular ions
• Ligand-gated ion channels are a receptor subtype
• Voltage-gated calcium channels (VOCC)
  • Calcium channels are involved in the contraction of smooth muscle cells and blood vessels
  • Increased calcium influx triggers the release of calcium from the sarcoplasmic reticulum (SERCA) pumps
  • Nifedipine is a blocker of L-type VOCCs
  • It reduces blood pressure by blocking calcium channels and preventing calcium release

Enzymes

• Enzymes can be blocked in the treatment of hypertension
• Renin angiotensin system (RAS) blockers
  • Angiotensin II (ANG 2) causes vasoconstriction, which increases blood pressure
  • Enalapril prevents the conversion of angiotensin I to angiotensin II by blocking the angiotensin-converting enzyme in the lungs

Transporters

• Responsible for the passage of ions and small molecules
• They have recognition sites
• Example: Selective Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine, sertraline and citalopram
  • Used to treat depression and anxiety
  • Patients with low serotonin levels benefit from SSRIs because these inhibitors block the reuptake of serotonin
  • The increased concentration of serotonin in the synapse prolongs its effect

Drug Selectivity Factors

• Drugs are rarely tissue/target selective and often have multiple tissue/receptor targets
• The usefulness of a drug is directly proportional to its binding site selectivity
  • Less selectivity leads to more adverse effects
• Lack of selectivity increases the risk of adverse effects
• Adverse effects from poor drug selectivity can be managed with:
  • Dose control
  • Using or developing more selective drugs
  • Changing administration routes (e.g. inhaling lung-targeted drugs instead of oral administration to reduce heart effects)

Drug Binding

• Factors that increase drug binding:
  • Increased drug concentration
  • Increased receptor concentration
• Factors that determine binding:
  • Receptor concentration [R]total
    • [R]total = [R] + [LR]
    • The direction of equilibrium depends on:
      • K1: Association complex
      • K-1: Dissociation complex
• Affinity:
  • A measure of the attraction of a ligand for its biological target
  • Represents the strength of binding
• KD: The ligand concentration when half of the receptors are occupied - High KD = low affinity (needs lots of drug to reach KD)
• High-affinity ligand: - Rapid binding for a long time - Results in many bound targets at lower concentrations compared to low-affinity ligands
• Efficacy:
  • The ability of a ligand to initiate cellular effects once bound to the target
  • Agonists: Full activation
  • Partial Agonists: Submaximal (Partial) activation
  • Antagonists: No activation

Drugs That Target β1-Adrenoceptors

• β1-adrenoceptors are found in the sympathetic nervous system, heart (SA/AV node, ventricles)
• When adrenaline or noradrenaline bind to these receptors, it increases heart rate and blood pressure
• Isoprenaline: Non-selective β1-adrenoceptor agonist
• It binds to multiple receptors, including β2-adrenoceptors
• Leads to increased heart rate and contractions due to its similar effect to noradrenaline
• Used for patients with heart block or arrhythmias
• Pindolol: Partial agonist of β1-adrenoceptors
  • It is an agonist but it decreases blood pressure
• It outcompetes noradrenaline in partially activating the receptors, leading to decreased full activation
• Metoprolol: Antagonist of β1-adrenoceptors (Beta-blocker)
  • Selective for β1-adrenoceptors
  • Inhibits the ability of noradrenaline to bind to receptors, preventing increased heart rate
• Used for hypertension

Drug Dose-Response Relationship

• Very high doses can make drugs non-selective, affecting unintended receptors
• Dose-Response Curves:
  • X-axis: Ligand concentration
  • Y-axis: Response as a percentage of the maximum effect the drug can produce
• Key parameters on dose-response curves:
  • Emax: Maximum effect of the drug in a given system
  • Potency: Drug concentration needed to produce the intended effect
  • Usually measured at 50% of the maximum effect
  • EC50: Potency of the drug at 50% of the maximum effect
  • High EC50: Low potency (more drug needed)

Agonist vs Partial Agonist

• Agonists have higher efficacy than partial agonists
• Because agonists can occupy less than 50% of receptors and still elicit a maximum response
• Partial agonists need to occupy more than 50% or all receptors to elicit the same response
  • EC50 ≥ KD: No spare receptors

Benefits of Partial Agonists

• Salbutamol: β2-adrenoceptor agonist
  • Used to dilate airways in asthma
  • Preferred over full agonists because it can cause desensitization of receptors by overstimulation
  • This limits the number of available receptors for long-term treatment
• Sumatriptan: 5-HT1A receptors agonist
  • Used for migraines
  • It constricts blood vessels associated with migraines
  • It is preferred over full agonists because it can cause vasoconstriction without affecting blood vessel constriction in the heart, preventing heart attacks

Antagonists

• Interfere with the interaction of agonists with receptor proteins or molecules
• Types of Antagonists:
  • Receptor Binding Site:
    • Reversible:
      • Competitive:
        • Naloxone: Competitive opioid receptor antagonist
          • It competes with opioid ligands
          • Reduces the potency (increased dose needed for the same effect) of agonists without affecting efficacy
          • Can be used for opioid overdose
      • Irreversible:
        • Omeprazole: Proton pump inhibitor
          • It binds irreversibly to the agonist binding site
          • It is used for heartburn to decrease acid concentration
          • Binds irreversibly to proton pumps and causes internalisation
          • New receptors are eventually recycled, so the effect is not permanent
    • Allosteric site:
    • Reversible:
      • Non-competitive allosteric: binds reversibly or irreversibly to the allosteric site
    • Irreversible:
      • Decreases the potency (not always) and efficacy of the agonist
      • The potency can remain the same
      • Efficacy can decrease
  • Non-receptor:
    • Chemical: - Protamine: Heparin antagonist
      • Heparin is an anticoagulant (thins blood)
      • Protamine breaks down heparin
    • Functional (Physiological): - Omeprazole: Against histamine
      • Used for heartburn
      • Histamine is expressed in parietal cells of the stomach lining and binds to receptors to increase acid secretion
      • Omeprazole binds to proton pumps and reduces their action
      • Histamine functions normally but acid production decreases
      • Non-competitive

Partial Agonists

• Partial agonists can act as antagonists in the presence of a full agonist
  • They bind to the same site as the agonist and outcompete the full activation of the agonist receptors
  • This leads to competitive antagonism
• Agonist + partial agonist = decreased potency of the agonist without affecting efficacy
• Partial agonist alone acts as a normal agonist
• Example: Pindolol: β2-adrenoceptor partial agonist

Targeting the Autonomic Nervous System (ANS)

• Potential for adverse effects
• Wide therapeutic opportunity
• Neuron structures:
  • Dendrites: Receive synaptic input
  • Soma: Housekeeping functions, including protein synthesis and processing
• Axon: Action potential conduction
• Pre-synaptic terminal: Converts electrical signals from action potentials into chemical signals (neurotransmitters)

Processing in the Nervous System

• Central nervous system (CNS) receives and integrates information from the internal and external environments via afferent sensory neurons - Brain: Within the meninges (dura mater) - Spinal cord comprises cervical, thoracic, lumbar, and sacral regions
• Peripheral nervous system (PNS) - Cranial nerves: Most nerves - Spinal nerves: All nerves - Peripheral ganglia - Sensory receptors
• CNS integrates information and responds to maintain homeostasis via efferent motor neurons and the PNS
• Tissues respond to feedback loops from the CNS