MEDC 603 Fall 2007 1

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
A. Transcription Factors (e.g., steroids,
vitamin D, retinoids)
B. Ligand Gated Ion Channels (e.g., GABA
A
,
glutamate, aspartate, glycine, etc)
C. G-Protein Coupled Receptors (GPCRs)
(e.g., neurotransmitters)
D. Enzyme-linked Receptors (e.g., kinases)
E. 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
OH
CH
3
O H
O
O O H O
OH
CH
3
O H
O
CH
3
OH
O H
CH C
C H
2
CH
2
O H C H
3
CH
3
OH
O
N
CH
3
CH
3
CH
2
C H
3
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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