MEDC 603 Fall 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 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 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., GABA A, 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)

MEDC 603 Fall Drugs and Drug Action  Typical Structure of a Receptor

MEDC 603 Fall 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 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 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 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 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