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Drugs and Drug Action. Definition – Drugs. Chemicals (not light, sound, radiation, magnetic field)…… fragrance? Prevent disease or assist in restoring health. History. Originated from natural products Examples include opium, belladonna, cinchona, marijuana, digitalis, quinine, ………….

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slide1

Drugs and Drug Action

  • Definition – Drugs
  • Chemicals (not light, sound, radiation, magnetic field)…… fragrance?
  • Prevent disease or assist in restoring health
  • History
  • Originated from natural products
  • Examples include opium, belladonna, cinchona, marijuana, digitalis, quinine, ………….
  • First use of synthetic organics …… ether and chloroform for anesthesia in 1830s
  • Structural derivatives …

MEDC 603 Fall 2007

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Drugs and Drug Action

  • Drug Action
  • Why do drugs work?

‘the hydrophobic effect?’ …. Lipophilicity was thought to be important

‘the medium effect?’ … generally changed conditions

‘the receptor effect?’ … Langley and Ehrlich’s hypothesis (1905)

  • The Receptor Hypothesis
  • Certain cells contain receptive substances that served as hosts for the drug molecules to bind
  • Example: pilocarpine was selective and potent for excitation of parasympathetic nervous system, while atropine was capable of blocking this effect! …… both interact with same component of the cell
  • ‘receptive’ substance  ‘receptor’
  • A macromolecule that recognizes ‘drugs’ through precise physicochemical and steric interactions

MEDC 603 Fall 2007

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Drugs and Drug Action

  • Receptor
  • Most drugs work through a receptor

e.g., testosterone or steroidal sex hormones; calcium channel blockers; growth factors; etc.

  • Few drugs work without a receptor being involved

e.g., EDTA (for lead poisoning); Mg(OH)2 for gastric acidity; mannitol for diuretic; etc.

  • Types of receptors

Membrane-bound

  • Transcription Factors (e.g., steroids, vitamin D, retinoids)
  • Ligand Gated Ion Channels (e.g., GABAA, glutamate, aspartate, glycine, etc)
  • G-Protein Coupled Receptors (GPCRs) (e.g., neurotransmitters)
  • Enzyme-linked Receptors (e.g., kinases)
  • Protease-Activated Receptors (e.g., thrombin-cleavage …; TNFa-converting enzyme)

MEDC 603 Fall 2007

slide4

Drugs and Drug Action

  • Typical Structure of a Receptor

MEDC 603 Fall 2007

slide5

Drugs and Drug Action

  • Typical Structure of a Receptor … e.g., GPCR

Bovine rhodopsin embedded in lipid bilayer with retinal (orange)

(K. Palczewski et al., Science 289, 739 (2000))

MEDC 603 Fall 2007

slide6

Drugs and Drug Action

  • Definition of a receptor is changing!
  • Free floating enzymes …… trypsin, thrombin, etc.
  • DNA and RNA …… cisplatin
  • Cell surface carbohydrates …… proteoglycans
  • Drug targets
  • Cellular receptors (52%)
  • Enzymes (28%)
  • Hormones and factors (11%)
  • DNA (2%)
  • Unknown (7%)

(from Drew, J. (2000) Science287, 1962)

MEDC 603 Fall 2007

slide7

Theory of Drug Action

  • Fischer’s ‘Lock and Key’ Hypothesis
  • Every ‘lock’ has its own ‘key’
  • If the ‘key’ is not precise, the ‘lock’ does not open
  • The ‘drug’ is the key that has to fit the target specifically and productively

MEDC 603 Fall 2007

slide8

Theory of Drug Action

  • Corollary of ‘Lock & Key’ Hypothesis
  • Does not explain why some ‘keys’ open doors partially? …… e.g., partial agonists or antagonists

MEDC 603 Fall 2007

slide9

Theory of Drug Action

  • Koshland’s ‘Induced-Fit’ Hypothesis
  • At least two steps …… e.g., step 1 is initial binding and step 2 is a change in structure of the receptor (and/or drug)
  • Receptor is flexible! …… can wrap around the drug …… the zipper model is extreme case of induced-fit
  • All intermediate cases do exist in nature

MEDC 603 Fall 2007