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 …

MEDC 603 Fall 2007 2

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

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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)

MEDC 603 Fall 2007 7

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