molecular basis of drug action - week 4

what can medicines interact with?

four major protein target families

• receptors → receive chemical signals

• enzymes → catalyze reactions

• ion channels → control ion movement

• transporters → move substances across membranes

ligand

A signalling molecule, drug, hormone, or cofactor that reversibly binds to a macromolecule (such as a protein, DNA strand, or cell receptor).

what is a receptor

• commonly a protein that recognizes a ligand and initiates or alters a biological response

• the endogenous ligand may be a neurotransmitter, hormone, cytokine or growth factor

• receptor activation is followed by signalling or direct change in cell behaviour

G proteins

G proteins (guanine nucleotide-binding proteins) are molecular switches inside cells that transmit signals from surface receptors to internal targets

four receptor classes

• G-protein-coupled receptors (GPCRs) activate G proteins and downstream effectors

• ligand-gated ion channels: ligand binding changes ion flow

• enzyme-linked receptors: activate intrinsic or associated enzymes

• intracellular/nuclear receptors: often regulate gene expression

cell-surface signalling

• an extracellular ligand binds to a receptor at the membrane

• the receptor activates intracellular signalling proteins

• effectors alter enzymes, transcription or cytoskeletal processes

• these changes become physiological response

intracellular receptors

• lipophilic ligands may cross cell membranes to reach intracellular receptors

• the ligand-receptor complex can influence transcription and protein synthesis

• effects may develop over hours because new gene products are needed

Agonist

• activating the receptor

• agonist binds a receptor (affinity) and activates it (efficacy)

• a drug can mimic an endogenous ligand or be natural ligand itself

Agonist in everyday clinical practice

• Salbutamol (agonist) activates β₂-adrenoceptors,
  promoting bronchodilation in asthma

• Insulin activates the insulin receptor, an
  enzyme-linked receptor, helping regulate
  glucose uptake and metabolism

• These are different receptor classes but
  share the idea of activation.

nasal decongestants

• Oxymetazoline, xylometazoline and
  phenylephrine are α-adrenoceptor agonists.

• They cause vasoconstriction in the nasal
  mucosa and temporarily reduce congestion.

• Clinical caution: excessive or prolonged
  topical use can cause rebound congestion.

  
  
  

antagonists

• binding without activation

• antagonists bind receptors but do not activate them as a agonists do

• a reversible competitive antagonist competes with the agonist at the same site

• non-competitive antagonism can arise by several mechanisms, including irreversible or allosteric interference

receptor antagonists in practice

• Propranolol blocks β-adrenoceptors; used
  for selected cardiovascular and other
  conditions.

• Tamoxifen is a selective oestrogen receptor
  modulator used in hormone-sensitive breast
  cancer.

• The same word “receptor” does not imply
  identical signalling or clinical effects.

Antihistamines: H₁ receptor effects

• Chlorphenamine and loratadine oppose
  histamine actions at H₁ receptors.

• Used for allergic symptoms such as
  sneezing, itching and hay fever.

  • Clinical comparison: chlorphenamine is
    more sedating than loratadine for many
    patients.

    
    

ion channels

blockers stop ion flow; modulators change the probability of a channel opening

ion channels as drug targets

• Ion channels are membrane proteins that
  permit selected ions to cross down
  electrochemical gradients.

• Opening or closing a channel changes
  electrical and cellular function.

  • Some drugs block conduction; others
    change channel gating.

    
    

channel blockers

• stopping permeation

• A pore blocker reduces the passage of ions
  through an ion channel

• Blocking Na⁺, Ca²⁺ or K⁺ movement can alter
  neuronal or cardiac signalling.

• Mechanism explains both benefit and
  toxicity of some medicines and toxins.

  
  
  

Calcium-channel blockers in cardiovascular care

• Amlodipine and nifedipine preferentially
  relax vascular smooth muscle.

• Verapamil and diltiazem also affect cardiac
  conduction and contractility.

• Members of the class can treat hypertension
  and angina; some can treat selected
  arrhythmias.

  
  
  

channel modulation: changing gating

• A modulator alters how likely a channel is to
  open or close.

• Changing ion movement changes
  excitability, secretion or muscle function.

• Channel modulation and channel pore
  blockade are not identical mechanisms.

  
  
  

Gliclazide: a channel drug for diabetes

• Sulfonylureas such as gliclazide close ATP-
  sensitive K⁺ channels in pancreatic β-cells.

• This triggers depolarisation, calcium entry
  and insulin release.

• Clinical consequence: insulin release can
  lead to hypoglycaemia, especially if meals
  are missed.

  
  

enzymes

• biological catalysts

• Enzymes accelerate reactions by converting
  substrates into products.

• Drug molecules may bind enzymes and
  change the reaction rate.

• Enzyme activity can be altered without the
  enzyme being a receptor.

  
  

enzyme inhibition: core patterns

• Competitive inhibitors typically bind at the
  substrate binding site.

• Non-competitive and allosteric inhibition
  change activity without simply competing for
  substrate binding.

• Inhibition may be reversible or irreversible;
  these distinctions are separate.

  
  
  

Cyclooxygenase Inhibition: Aspirin & Ibuprofen

• Cyclooxygenase (COX-1/COX-2) enzymes
  participate in prostaglandin synthesis.

• Ibuprofen is a reversible COX inhibitor;
  reduced prostaglandins explain analgesic
  and anti-inflammatory effects.

• Aspirin irreversibly acetylates COX; its
  antiplatelet action is especially important
  clinically.
  
  

prodrugs

• activation happens later

• A prodrug requires chemical or enzymatic
  conversion to yield its active form.

• Prodrug design may improve absorption,
  distribution or tolerability.

• Do not confuse an enzyme that activates a
  prodrug with the final pharmacological
  target.

  
  

Enalapril And Codeine: Activation Matters

• Enalapril is converted by esterases to
  enalaprilat, the active ACE inhibitor.

• Codeine is partly converted by CYP2D6 to
  morphine.

• Genetic variation in CYP2D6 can lead to
  altered codeine response and toxicity risk.

  
  
  

false substrates: different strategy

• A false substrate is processed by an enzyme
  into a product that changes a downstream
  pathway.

• The enzyme need not be inhibited by the
  drug itself.

  
  
  

methyldopa

• unusual pharmacology pathway

• Methyldopa is converted to α-
  methylnoradrenaline by metabolic enzymes.

• The active product acts centrally at α₂-
  adrenoceptors, reducing sympathetic
  outflow.

• This provides an example of a false substrate/ converted product, rather than simple
  enzyme inhibition.

  
  
  

transporters as targets

• Transporters move ions and organic
  molecules across membranes.

• Many transporters couple movement to
  concentration gradients or ATP.

• Inhibiting uptake can increase extracellular
  transmitter availability.

  
  
  

transport inhibitors

• blocking uptake

• A transporter inhibitor decreases movement
  through a transporter.

• This differs from receptor antagonism: the
  transporter moves a substance rather than
  detecting a signal.

• The final effect may still arise because more
  transmitter stimulates receptors.

  
  
  

fluoxetine

• Fluoxetine is a selective serotonin reuptake
  inhibitor (SSRI).

• It inhibits the serotonin transporter (SERT) on
  presynaptic neurons.

• Less serotonin is taken back up, increasing its
  availability in the synaptic cleft.

• Clinical antidepressant response develops over
  time; do not equate immediate SERT inhibition
  with immediate mood improvement

amphetamines

• Amphetamine-like compounds interact with
  monoamine transporters and can increase
  extracellular monoamines.

• These agents act differently from simple
  reuptake inhibition and can also promote
  transmitter release.

• Clinical relevance includes selected ADHD
  treatments; misuse carries cardiovascular
  and psychiatric risks.