Drugs and Drug Action

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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, .
• First use of synthetic organics ether and
  chloroform for anesthesia in 1830s
• Structural derivatives

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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 Ehrlichs
  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

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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)

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Drugs and Drug Action

• Typical Structure of a Receptor

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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))
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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) Science 287,
  1962)

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Theory of Drug Action

• Fischers 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

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Theory of Drug Action

• Corollary of Lock Key Hypothesis

• Does not explain why some keys open doors
  partially? e.g., partial agonists or
  antagonists

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Theory of Drug Action

• Koshlands 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