MEDC 603 Fall 2007

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Medications and Drug Action Definition – Drugs Chemicals (not light, stable, radiation, attractive field)… … scent? Avert sickness or help with reestablishing wellbeing History Originated from common items Examples incorporate opium, belladonna, cinchona, maryjane, digitalis, quinine, … . Initially utilization of manufactured organics … ether and chloroform for anesthesia in 1830s Structural subordinates … MEDC 603 Fall 2007

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Drugs and Drug Action Drug Action Why do drugs work? 'the hydrophobic impact?' … . Lipophilicity was thought to be essential 'the medium impact?' … for the most part changed conditions 'the receptor impact?' … Langley and Ehrlich's speculation (1905) The Receptor Hypothesis Certain cells contain responsive substances that served as hosts for the medication atoms to tie Example: pilocarpine was particular and powerful for excitation of parasympathetic sensory system, while atropine was equipped for hindering this impact! … both associate with same part of the cell "responsive" substance ��  "receptor" A macromolecule that perceives "drugs" through exact physicochemical and steric communications MEDC 603 Fall 2007

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Drugs and Drug Action Receptor Most medications work through a receptor e.g., testosterone or steroidal sex hormones; calcium channel blockers; development components; and so on. Few medications work without a receptor being included e.g., EDTA (for lead harming); Mg(OH)2 for gastric sharpness; mannitol for diuretic; and so on. Sorts of receptors Membrane-bound Transcription Factors (e.g., steroids, vitamin D, retinoids) Ligand Gated Ion Channels (e.g., GABA A , glutamate, aspartate, glycine, and so on) G-Protein Coupled Receptors (GPCRs) (e.g., neurotransmitters) Enzyme-connected Receptors (e.g., kinases) Protease-Activated Receptors (e.g., thrombin-cleavage … ; TNF a - changing over catalyst) MEDC 603 Fall 2007

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

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Drugs and Drug Action Typical Structure of a Receptor … e.g., GPCR Bovine rhodopsin implanted in lipid bilayer with retinal (orange) (K. Palczewski et al., Science 289, 739 (2000)) MEDC 603 Fall 2007

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Drugs and Drug Action Definition of a receptor is evolving! Free gliding compounds … trypsin, thrombin, and so on. DNA and RNA … cisplatin Cell surface starches … proteoglycans Drug targets Cellular receptors (52%) Enzymes (28%) Hormones and variables (11%) DNA (2%) Unknown (7%) (from Drew, J. (2000) Science 287 , 1962) MEDC 603 Fall 2007

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Theory of Drug Action Fischer's 'Bolt and Key' Hypothesis Every "bolt" has its own "key" If the "key" is not exact, the "bolt" does not open The "medication" is the key that needs to fit the objective particularly and beneficially MEDC 603 Fall 2007

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Theory of Drug Action Corollary of 'Bolt & Key' Hypothesis Does not clarify why some "keys" open entryways incompletely? … e.g., halfway agonists or enemies MEDC 603 Fall 2007

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Theory of Drug Action Koshland's 'Actuated Fit' Hypothesis At minimum two stages … e.g., step 1 is beginning authoritative and step 2 is an adjustment in structure of the receptor (or potentially sedate) Receptor is adaptable! … can wrap around the medication … the zipper model is outrageous instance of instigated fit All middle cases do exist in nature MEDC 603 Fall 2007