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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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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
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 MEDC 603 Fall 2007
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) MEDC 603 Fall 2007
Drugs and Drug Action • Typical Structure of a Receptor MEDC 603 Fall 2007
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)) MEDC 603 Fall 2007
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) Science287, 1962) MEDC 603 Fall 2007
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 MEDC 603 Fall 2007
Theory of Drug Action • Corollary of ‘Lock & Key’ Hypothesis • Does not explain why some ‘keys’ open doors partially? …… e.g., partial agonists or antagonists MEDC 603 Fall 2007
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 MEDC 603 Fall 2007
