Drug-Receptor Interactions

Drug-Receptor Interactions

Understanding drug-receptor interactions is the mechanistic foundation of pharmacology. Drugs produce their effects by binding to specific molecular targets — receptors, enzymes, transporters, or ion channels — and altering cellular function. This lesson focuses on receptor classification, the pharmacological consequences of binding, and the quantitative parameters that describe drug action.

Types of Drug Receptors

1. G-protein-coupled receptors (GPCRs)

GPCRs are the largest family of drug targets, comprising over 800 human genes. They are seven-transmembrane (7-TM) proteins coupled to heterotrimeric G-proteins (Gα, Gβ, Gγ). Ligand binding induces a conformational change activating the Gα subunit, which exchanges GDP for GTP and dissociates to modulate effectors:

• Gs (stimulatory): activates adenylyl cyclase → ↑cAMP → PKA activation. Examples: β1-adrenoceptor (heart rate ↑), β2-adrenoceptor (bronchodilation), glucagon receptor.
• Gi (inhibitory): inhibits adenylyl cyclase → ↓cAMP. Examples: α2-adrenoceptor, M2 muscarinic, opioid receptors.
• Gq: activates phospholipase C-β → IP3 (↑intracellular Ca²⁺) + DAG (→ PKC activation). Examples: M1/M3 muscarinic, α1-adrenoceptor, H1 histamine.
• G12/13: activates RhoGEF → cytoskeletal changes, vasoconstriction.

GPCRs are subject to desensitisation: prolonged agonist exposure activates GPCR kinases (GRKs) → phosphorylation → β-arrestin binding → receptor internalisation (endocytosis). This explains tolerance to opioids and beta-agonists.

2. Ligand-gated ion channels (LGICs)

LGICs mediate the fastest drug responses (milliseconds) because ligand binding directly opens an integral ion channel — no second messenger required. Key examples:

• nACh receptor: pentameric (α2βγδ); Na⁺/K⁺ influx → depolarisation → muscle contraction. Blocked by competitive antagonists (tubocurarine) or depolarising blockers (suxamethonium).
• GABA-A receptor: pentameric; Cl⁻ influx → hyperpolarisation → inhibition. Modulated (not activated) by benzodiazepines (increase Cl⁻ channel opening frequency) and barbiturates (increase duration). Activated by GABA, blocked by bicuculline.
• NMDA receptor: ligand-gated Ca²⁺/Na⁺ channel; requires simultaneous glutamate AND glycine binding, plus Mg²⁺ unblock (voltage-dependent). Blocked by ketamine (anaesthetic/analgesic) and memantine (Alzheimer's therapy).
• 5-HT3 receptor: Na⁺/K⁺ influx; blocked by ondansetron (antiemetic).

3. Receptor tyrosine kinases (RTKs)

RTKs mediate the effects of peptide hormones and growth factors. Ligand binding promotes receptor dimerisation and trans-autophosphorylation of intracellular tyrosine residues, initiating PI3K/Akt, MAPK/ERK, and JAK-STAT cascades (minutes). Examples: insulin receptor (glucose uptake), EGFR (epithelial growth), VEGFR (angiogenesis). Clinically targeted by imatinib (BCR-ABL), gefitinib (EGFR), and trastuzumab (HER2).

4. Nuclear receptors

Nuclear receptors are ligand-activated transcription factors; effects develop over hours to days. The two main subfamilies are:

• Type I (steroid receptors): reside in cytoplasm; ligand binding → nuclear translocation → homodimerisation → DNA binding at hormone response elements (HREs). Examples: glucocorticoid receptor (cortisol, dexamethasone), androgen receptor, oestrogen receptor (ERα/ERβ). Tamoxifen and raloxifene are selective ER modulators (SERMs).
• Type II (non-steroid): reside in nucleus bound to DNA; ligand binding releases co-repressors and recruits co-activators. Examples: thyroid hormone receptor, vitamin D receptor (VDR), PPAR (peroxisome proliferator-activated receptor — target of fibrates and thiazolidinediones).

Agonists and Antagonists

Full agonist: Binds and activates the receptor to produce maximum possible effect (Emax = 100%). High intrinsic efficacy (ε = 1). Examples: morphine at μ-opioid receptor; adrenaline at β-adrenoceptors; acetylcholine at muscarinic receptors.

Partial agonist: Binds receptor but has intrinsic efficacy less than 1, so even at 100% receptor occupancy it produces submaximal Emax. Can act as a functional antagonist in the presence of a full agonist (by competing for binding while producing less response). Clinically important examples:

• Buprenorphine (μ-opioid partial agonist): ceiling effect on respiratory depression makes it safer in opioid substitution therapy; high receptor affinity means naloxone reversal requires higher doses.
• Buspirone (5-HT1A partial agonist): anxiolytic without benzodiazepine dependence.
• Aripiprazole (D2 partial agonist): second-generation antipsychotic.

Competitive (surmountable) antagonist: Binds reversibly to the same site as the agonist; increases EC50 (parallel right-shift of dose-response curve) but Emax is unchanged because sufficient agonist can displace the antagonist. Examples: propranolol (β-adrenoceptor); naloxone (μ-opioid); atropine (muscarinic M1-M5).

Non-competitive (insurmountable) antagonist: Binds irreversibly or at an allosteric site; reduces Emax regardless of agonist concentration. Emax depression is not overcome by adding more agonist. Examples: phenoxybenzamine (irreversible α-adrenoceptor); organophosphates (irreversible AChE inhibition — causes excess ACh effects).

Inverse agonist: Binds the receptor and produces an effect opposite to that of an agonist; decreases constitutive (basal) receptor activity below baseline. Distinct from an antagonist, which simply blocks agonist-induced activity. Example: some antihistamines at H1 receptors are inverse agonists rather than neutral antagonists.

Dose-Response Relationships: Key Parameters

Graded dose-response curve (continuous): Plots response (%) on y-axis vs log[drug concentration] on x-axis; typically sigmoid shape.

• EC50 (effective concentration 50%): Concentration producing 50% of Emax; primary measure of potency. Lower EC50 = more potent.
• Emax: Maximum possible effect; measure of efficacy.
• Hill coefficient (n): Slope of the log-linear portion; >1 indicates cooperativity.

Potency vs Efficacy distinction (clinically critical):

• A drug can be highly potent (very low EC50) but have low efficacy (low Emax). Codeine is less efficacious than morphine (lower Emax for analgesia) but not less potent in the same sense.
• Buprenorphine has higher receptor affinity (lower Kd) than morphine but lower intrinsic efficacy (partial agonist) — explains the analgesic ceiling.

Quantal dose-response (all-or-none): Used for population effects. ED50 = dose effective in 50% of population. LD50 = lethal dose in 50%. Therapeutic index (TI) = LD50/ED50. Drugs with narrow TI (e.g., digoxin, lithium, warfarin, aminoglycosides, phenytoin) require therapeutic drug monitoring (TDM).

Spare receptors (receptor reserve): Emax can be achieved when only a fraction of receptors are occupied. Spare receptors amplify sensitivity (Emax achieved at much lower [agonist] than needed to occupy all receptors) and buffer against receptor down-regulation.

Structure-Activity Relationships in Receptor Binding

Key physicochemical features determining receptor binding:

1. Charge and ionisation state: The ionic form of a drug determines whether it can interact with charged residues in the binding pocket. Adrenaline's protonated amine forms a salt bridge with Asp113 in the β2-adrenoceptor.
2. Hydrogen bonding capacity: H-bond donors and acceptors interact with complementary residues. Catecholamines form H-bonds with Ser204 and Ser207 in TM5 of β2-adrenoceptor.
3. Hydrophobic/aromatic interactions: π-stacking and hydrophobic contacts in the binding pocket. Phenethylamine scaffold provides aromatic ring π-stacking.
4. Stereochemistry: Receptor binding is often highly stereoselective. L-adrenaline is ~50× more potent than D-adrenaline. S-salbutamol is the active enantiomer (R,R-formoterol is more active than S,S).
5. Molecular size and shape: Must fit the binding pocket; too large = steric clash; too small = suboptimal contacts.

Receptor Regulation

Desensitisation and down-regulation: Prolonged agonist exposure → GRK phosphorylation → β-arrestin binding → receptor internalisation → short-term desensitisation. With chronic exposure: receptor degradation (down-regulation) → reduced total receptor number. Clinical relevance: β2-agonist tolerance in asthma; opioid tolerance; GPCR-targeted drug development.

Up-regulation: Prolonged antagonist therapy → reduced stimulation → compensatory receptor up-regulation. Critical with beta-blockers — abrupt withdrawal can precipitate rebound tachycardia/angina due to sudden agonist (adrenaline) access to up-regulated receptors. Always taper beta-blockers.