medc 603 fall 20071 drugs and drug action definition – drugs chemicals (not light, sound,...
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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 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
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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 involvede.g., EDTA (for lead poisoning); Mg(OH)2 for gastric acidity; mannitol for diuretic; etc.
Types of receptorsMembrane-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 …; TNF-converting enzyme)
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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
Does not explain why some ‘keys’ open doors partially? …… e.g., partial agonists or antagonists
OHCH3
OH
O
OOH O
OH
CH3
OH
OCH3
OH
OH
CHC
CH2
CH2OH CH3
CH3 OH
O
N
CH3
CH3CH2CH3
MEDC 603 Fall 2007 9
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