Drugs and Drug Action q Definition Drugs Chemicals

Drugs and Drug Action q Definition – Drugs ü Chemicals (not light, sound, radiation, magnetic field)…… fragrance? ü Prevent disease or assist in restoring health q History ü Originated from natural products ü Examples include opium, belladonna, cinchona, marijuana, digitalis, quinine, …………. ü First use of synthetic organics …… ether and chloroform for anesthesia in 1830 s ü Structural derivatives … MEDC 603 Fall 2007 1

Drugs and Drug Action q Drug Action ü 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) q The Receptor Hypothesis ü Certain cells contain receptive substances that served as hosts for the drug molecules to bind ü 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 ü ‘receptive’ substance ‘receptor’ ü A macromolecule that recognizes ‘drugs’ through precise physicochemical and steric interactions MEDC 603 Fall 2007 2

Drugs and Drug Action q Receptor ü Most drugs work through a receptor e. g. , testosterone or steroidal sex hormones; calcium channel blockers; growth factors; etc. ü Few drugs work without a receptor being involved e. g. , EDTA (for lead poisoning); Mg(OH)2 for gastric acidity; mannitol for diuretic; etc. ü 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. , thrombincleavage …; TNFa-converting enzyme) MEDC 603 Fall 2007 3

Drugs and Drug Action q Typical Structure of a Receptor MEDC 603 Fall 2007 4

Drugs and Drug Action q 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 q Definition of a receptor is changing! ü Free floating enzymes …… trypsin, thrombin, etc. ü DNA and RNA …… cisplatin ü Cell surface carbohydrates …… proteoglycans q Drug targets ü ü ü 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 q Fischer’s ‘Lock and Key’ Hypothesis ü ü ü 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 q Corollary of ‘Lock & Key’ Hypothesis ü Does not explain why some ‘keys’ open doors partially? …… e. g. , partial agonists or antagonists MEDC 603 Fall 2007 8

Theory of Drug Action q Koshland’s ‘Induced-Fit’ Hypothesis ü 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) ü Receptor is flexible! …… can wrap around the drug …… the zipper model is extreme case of induced-fit ü All intermediate cases do exist in nature MEDC 603 Fall 2007 9