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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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First use of synthetic organics …… ether and
chloroform for anesthesia in 1830s
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Structural derivatives …
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Drugs and Drug Action
 Drug Action
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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
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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
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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.,
GABAA, 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
 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
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Theory of Drug Action
 Corollary of ‘Lock & Key’ Hypothesis
O
CH3
CH3 OH
HO
CH3 OH
C
HO
HO
OH
O
HO
O
O
O
H3C
CH2
N
CH3
H2C
CH3
CH3
HO

H3C
CH2
Does not explain why some ‘keys’ open doors partially?
…… e.g., partial agonists or antagonists
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OH
CH
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
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