Drug Receptors - Pharmacology (Second MBBS)

1. DEFINITION OF A RECEPTOR

"Receptors have become the central focus of investigation of drug effects and their mechanisms of action (pharmacodynamics)."

• Katzung's Basic and Clinical Pharmacology, 16th ed., p. 44

2. IMPORTANCE OF THE RECEPTOR CONCEPT

1. Quantitative relations - The receptor's affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors limits the maximal effect.
2. Selectivity of drug action - Molecular size, shape, and electrical charge of a drug determine whether - and with what affinity - it will bind to a particular receptor. Changes in chemical structure can dramatically alter affinities for different receptor classes.
3. Mediating agonist and antagonist actions - Drugs either activate receptors (agonists) or bind without activating (antagonists), blocking agonist access.

3. MACROMOLECULAR NATURE OF DRUG RECEPTORS

4. CLASSIFICATION OF RECEPTORS (Major Classes)

Class I - G Protein-Coupled Receptors (GPCRs)

• Also called metabotropic or 7-transmembrane (7-TM) receptors
• Signal via heterotrimeric G proteins (Gs, Gi, Gq, G12/13)
• Examples of ligands: Adrenaline, acetylcholine (muscarinic), histamine, serotonin, dopamine, glucagon
• Second messengers generated:
  • Gs - stimulates adenylyl cyclase → ↑cAMP → activates PKA
  • Gi - inhibits adenylyl cyclase → ↓cAMP
  • Gq - activates phospholipase C-β → ↑IP3 + DAG → ↑Ca2+ + PKC activation
• Response time: Seconds to minutes
• Drug examples: Propranolol (β-blocker), salbutamol (β2-agonist), atropine (muscarinic antagonist)

Class II - Ligand-Gated Ion Channels (LGICs)

• Also called ionotropic receptors
• The receptor IS the ion channel - binding opens/closes the channel directly
• Structure: Nicotinic acetylcholine receptor (nAChR) is a pentamer - 2α + 1β + 1γ + 1δ subunits, crossing the lipid bilayer 4 times each, forming a 10 nm diameter cylinder
• When ACh binds to α subunits: Central aqueous channel (~0.5 nm) opens → Na+ flows in → depolarization (EPSP)
• Response time: Milliseconds (fastest signaling)
• Examples:
  • nAChR - Na+/K+ (excitatory)
  • GABA-A receptor - Cl- (inhibitory)
  • NMDA/AMPA glutamate receptors - Na+/K+/Ca2+
  • Glycine receptors - Cl-
  • 5-HT3 receptor - Na+/K+
• Drug examples: Benzodiazepines (enhance GABA-A Cl- influx), succinylcholine (nAChR agonist), curare (nAChR antagonist)

Class III - Enzyme-Linked (Catalytic) Receptors

• Receptor itself has intrinsic enzymatic activity (usually tyrosine kinase)
• Receptor Tyrosine Kinases (RTKs):
  • Ligand binding causes dimerization → autophosphorylation → activates downstream signaling (SH2 domains, MAPK, PI3K/Akt)
  • Ligands: Insulin, EGF, PDGF, VEGF, growth factors
  • Response: Minutes to hours
  • Drug examples: Imatinib (BCR-ABL tyrosine kinase inhibitor), trastuzumab (HER2 receptor blocker)
• Other subtypes:
  • Receptor serine/threonine kinases (TGF-β → SMADs)
  • Membrane-bound guanylyl cyclase (natriuretic peptides → cGMP)
  • Cytokine receptors (interleukins, growth hormone → JAK/STAT)

Class IV - Nuclear Receptors (Intracellular Receptors)

• Located in cytoplasm or nucleus; ligand must be lipid-soluble to cross the cell membrane
• Drug-receptor complex acts as a transcription factor → alters gene expression
• Response time: Hours (gene transcription → new protein synthesis)
• Ligands/drugs: Corticosteroids, sex hormones (estrogen, testosterone), thyroid hormone, vitamin D, retinoic acid
• Clinical note: Tamoxifen is a selective estrogen receptor modulator (SERM) - acts as an antagonist in breast tissue but agonist in bone (tissue-specific receptor accessory proteins explain this selectivity)

5. DOSE-RESPONSE RELATIONSHIPS

Graded Dose-Response Curve

• Plots drug effect (as % maximal response) on Y-axis vs. log dose on X-axis
• Gives a sigmoidal (S-shaped) curve
• Key parameters:
  • Emax - Maximum effect achievable
  • EC50 (or ED50) - Concentration that produces 50% of maximal effect (measure of potency)

Potency vs. Efficacy

A drug can be highly potent but have low efficacy - e.g., a partial agonist may need less drug to reach its ceiling, but that ceiling is lower than a full agonist.

6. AGONISTS AND ANTAGONISTS

Agonist

• Binds receptor AND activates it (mimics the natural ligand)
• Full agonist - Produces maximal possible response (Emax = 100%)
• Partial agonist - Even at full receptor occupancy, produces submaximal response (e.g., buprenorphine at opioid receptors)
• Inverse agonist - Binds receptor and produces the opposite effect to an agonist (constitutive activity suppressed)

Antagonist

• Binds receptor but does NOT activate it; blocks agonist access
• Competitive (reversible) antagonist:
  • Competes with agonist at same binding site
  • High agonist concentrations can overcome blockade
  • Shifts dose-response curve to the RIGHT (higher EC50), but Emax is unchanged
  • Example: Propranolol (β-receptor), atropine (muscarinic)
• Non-competitive (irreversible) antagonist:
  • Binds receptor at a different site (allosteric) or permanently (covalent bond)
  • Cannot be overcome by increasing agonist concentration
  • Reduces Emax (shifts curve downward)
  • Example: Phenoxybenzamine (α-blocker - covalent)

Allosteric Modulator

• Binds to a site DIFFERENT from the agonist site
• Can be positive (enhances agonist effect) or negative (reduces it)
• Example: Benzodiazepines are positive allosteric modulators of GABA-A receptors

7. SPARE RECEPTORS (Receptor Reserve)

• Maximal biological response can be elicited even when only a FRACTION of total receptors are occupied
• Example: Cardiac muscle can show maximal inotropic response to catecholamines even when 90% of β-adrenoceptors are blocked
• Significance: The sensitivity of a cell depends on both receptor affinity (Kd) AND the proportion of spare receptors

8. RECEPTOR REGULATION

Down-regulation (Desensitization/Tachyphylaxis)

• Prolonged exposure to an agonist → decrease in receptor number or sensitivity
• Mechanisms:
  • Receptor phosphorylation (uncouples G-protein)
  • Receptor internalization (endocytosis)
  • Decreased receptor synthesis
• Clinical example: β2-agonist tolerance in asthma (prolonged salbutamol use)

Up-regulation (Supersensitivity)

• Prolonged exposure to an antagonist or denervation → increase in receptor number
• Clinical importance: Abrupt withdrawal of β-blockers can cause rebound tachycardia/angina due to up-regulated β-receptors now exposed to normal catecholamines

9. RECEPTOR SELECTIVITY AND DRUG DEVELOPMENT

• Same ligand can act on different receptor subtypes: ACh acts on both nicotinic (ion channel) and muscarinic (GPCR) receptors
• Receptor subtypes allow selective drug targeting:
  • Propranolol (β1+β2 block) vs. metoprolol (selective β1)
  • α1 vs. α2 adrenoceptors
• Multiple receptor subtypes arise from evolution - providing drug development opportunities

10. G PROTEINS AND SECOND MESSENGERS (Signaling Cascade)

• IP3 → releases Ca2+ from ER → activates calmodulin-dependent kinases
• DAG → activates PKC

11. VOLTAGE-GATED ION CHANNELS AS DRUG TARGETS

• Not directly gated by ligand binding - controlled by membrane potential
• Important targets for:
  • Local anaesthetics (e.g., lidocaine) - block voltage-gated Na+ channels
  • Calcium channel blockers (e.g., verapamil, nifedipine) - block L-type Ca2+ channels
  • Antiepileptics (e.g., phenytoin) - block Na+ channels

12. SUMMARY TABLE: RECEPTOR CLASSES

EXAM-STYLE QUICK POINTS

• Nicotinic receptor structure: Pentamer (2α1β1γ1δ), ligand-gated Na+ channel, fastest response
• Spare receptors: Maximal response without full receptor occupancy - buffer against receptor loss
• Competitive antagonist: Shifts curve RIGHT, Emax unchanged, reversible by excess agonist
• Non-competitive antagonist: Reduces Emax, curve shifts DOWN
• Down-regulation: Prolonged agonist exposure → tolerance (e.g., β2-agonist in asthma)
• Up-regulation: Prolonged antagonist → rebound on withdrawal (e.g., β-blocker withdrawal)
• Inverse agonist: Opposes constitutive receptor activity (e.g., some H1 antihistamines)
• Partial agonist: Can act as functional antagonist in presence of a full agonist (e.g., buprenorphine)
• SERM concept (Tamoxifen): Antagonist in breast, agonist in bone - tissue specificity via accessory proteins