Week 5

• Adrenergic messenger chemicals


  The hormone adrenaline & the neurotransmitter noradrenaline
• Adrenergic receptor site


  • Key interactions for messenger binding
• Structure activity relationship (SAR) studies

  Can direct a research program
• Adrenoreceptors


  Agonists or antagonists at α and β-adrenoreceptors result in a variety of physiological effects
• Endogenous agonists


  noradrenaline, adrenaline
• Metabolism of adrenergic messenger chemicals

  1. MAO: monamine oxidase

  2. COMT: catechol O-methyl transferase
• Adrenergic binding site


  • Key interactions: hydrophobic residues, H-bonding, ionic interaction
• Adrenergic receptors


  • α
  • β1
  • β2
  • β3
• Distribution & effects of adrenergic receptors

  α: contracts smooth muscle (not in the gut)

  β1: contracts cardiac muscle

  β2: relaxes smooth muscle (airways)

  β3: fat metabolism; relaxes smooth muscle (bladder)
• Receptor-selective drugs


  Act selectively at different organs or tissues
• Agonist


  Mimic natural messengers, bind & leave quickly, receptor activated
• Antagonist


  Block natural messengers, have strong &/or more binding interactions, receptor NOT activated
• Adrenoreceptors


  Split into 𝛼 and �� subclasses, which are further divided into sub-types 𝛼1, 𝛼2, 𝛽1, 𝛽2
• Activation of different adrenoreceptors


  Results in a variety of physiological effects
• Structure-activity relationship (SAR) studies

  • Can direct a research program
• Structural changes


  • Lead to 𝛼 or 𝛽 selectivity
• Approaches to suggest potential research strategies

  To access new drugs that selectively target 1) 𝛼-adrenoreceptors; 2) 𝛽-adrenoreceptors; 3) 𝛽1-adrenoreceptors or 4) 𝛽2-adrenoreceptors
• Identifying adrenoreceptor subclass or sub-type a drug molecule will have activity at

  Predicting the outcome of this interaction (agonist or antagonist)
• Selectivity


  𝛼 vs 𝛽
• First generation 𝛽-blockers


  • Isoprenaline
  • Dichloroisoprenaline
  • Pronetalol
  • Propranolol
  • Pindolol
  • Timolol
• Structural changes for 𝛽1-selectivity

  • Chain extension
  • Spacer added
  • Position varied
  • Branched to fit hydrophobic pocket
  • Must be 2ᵒ
  • HBD essential
  • HBA
  • Equivalent substitution OK
• Toolkit for 𝛽2-agonists


  • Additional functional groups: interactions; agonist vs antagonist
  • Chain extension: new binding pockets?
  • Vary position of substituents: optimize binding?
  • Chiral switch: 1 enantiomer or racemate?
  • Bioisosteres: replace equivalent F.G. @ key binding site