Drugs and Drug Action Definition Drugs Chemicals (not

Drugs and Drug Action  Definition  Drugs Chemicals (not

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 1 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 MEDC 603 Fall 2007 2 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., 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 ; TNFconverting enzyme) MEDC 603 Fall 2007 3 Drugs and Drug Action Typical Structure of a Receptor MEDC 603 Fall 2007 4 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 5 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 6 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 MEDC 603 Fall 2007 7 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 MEDC 603 Fall 2007 8 OH CH

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 MEDC 603 Fall 2007 9

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