Class20 - Chemistry 83 Technologies Associated with...

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Unformatted text preview: Chemistry 83 Technologies Associated with Pharmaceu<cals (Drugs) Drug is a substance, other than food or water, that affects how a body func<ons. Drugs having a posi<ve effect are called medicines. How do drugs func<on (pharmacodynamics)? Simplis<cally, a drug func<ons as an on/off switch for a biological func<on. The biological molecule is called a receptor. The drug and receptor must have regions of complementary structures and intermolecular forces so that they will be aIracted to and combine with each other to form a drug ­receptor complex. Complementary structures Complementary intermolecular forces Schaumberg, Concerning Chemistry, Wiley,NY,1974,226 and 229 Class20 1 Chemistry 83 The drug ­receptor complex turns the biological func<on on or off ON SWITCH Agonist  ­ drug that ac<vates a cell receptor by fiOng the receptor and mimicking the natural substrate OFF SWITCH Antagonist  ­ drug that deac<vates a cell receptor by fiOng the receptor and blocking it from its natural substrate Staniski et al, Chemistry in Context,4th,McGraw Hill, IA,2003, 407 Carboxypeptidase-A ! A second type of receptor is an enzyme OFF SWITCH The drug fits the ac<ve site of the enzyme and then remains in the site blocking the natural substrate molecule from carrying out its biological func<on. This type of drug is called an enzyme inhibitor. Zumdahl, Chemical principles, Heath,MA, 1992, 697 Class20 2 Chemistry 83 Where do drugs come from? Suchocki,J.,”Conceptual Chemistry”, 3rd, Pearson,Boston,2007,480 Medicinal chemistry is concerned with the discovery, identification, synthesis, development of new drugs and optimization of existing drugs •  Example: drug known since 400 BC •  Hippocrates, Father of Medicine, used an extract, prepared by boiling bark from a willow tree in water, to reduce fevers and pain •  This folk remedy was used for centuries, but was not scien<fically studied un<l 1827 when an ac<ve component, salicin, was isolated Snyder, Extraordinary Chemistry, Wiley, NY, 1992, 604 Class20 3 Chemistry 83 Salicin from willow bark reacts with water to produce glucose and salicyl alcohol. In humans, salicyl alcohol is oxidized to salicylic acid which is the ac<ve substance that reduces fever (an< ­pyre<c), pain (analgesic), and inflamma<on (an< ­ inflammatory agent). Snyder, Extraordinary Chemistry, Wiley, NY, 1992, 605 Although salicylic acid reduces pain, fever, and inflamma<on, it is far too corrosive to <ssues in the stomach to be taken internally by most people. In 1893 Felix Hofman, a chemist working for the Bayer firm in Germany, converted salicyclic acid to acetylsalicylic acid which can be beIer tolerated by most people. 80 B tablets/yr sold in US Snyder, Extraordinary Chemistry, Wiley, NY, 1992, 606 Class20 4 Chemistry 83 Synthe<c analgesics are based on the structure of aspirin Medicinal chemists synthesize drugs that have the same key donor groups in the same rela<ve loca<ons in their structures. These likely will exhibit similar biological ac<vi<es.(QSAR  ­ Quan<ta<ve Structure Ac<vity Rela<ons) Aspirin has a benzene ring and C=O separated by one atom. Aspirin Ibuprofen (Advil, Motrin) 1960 Naproxen (Aleve) 1980 Acetaminophen (Tylenol, Datril) 1955 Suchocki, Chemistry, 2nd, Benjamin, 2004, 486 How are drugs tested by Food and Drug Administra<on prior to approval? It takes 12 years on average for an experimental drug to travel from lab to medicine chest. Phase IV may also involve law suits due to problems that show up only on long term use. Process makes drugs safe but expensive. Class20 5 Chemistry 83 Part of tes<ng determines pharmacokine<cs  ­ determining what the body does to a drug respirable drug ABSORPTION inhalation drug on skin skin (dermal) drug in eye intravenous intramuscular subcutaneous eye lung blood and lymphatic systems alveoli DISTRIBUTION/ METABOLISM alveoli lung central nervous system swallowing drug injection kidney ingestion * liver fat gastro- intestinal tract bile glands and Fetus and secretory other structures target organs bladder EXCRETION expired air urine secretions including sweat and breast milk feces *Liver is the bodyʼs “detox” factory. Reactions in liver usually make it easier for the body to eliminate drug such as oxidation to make toxin more water soluble (exits in urine).! Tes<ng also determines side effects and dosage (g) ED50, effective dose - dose that produces therapeutic effect in 50% of test subjects (above graph: 100 mg) TD50, toxic dose - dose that produces specific unwanted side-effect in 50% of test subjects (above = ?) Therapeutic index, TI = TD50/ED50; Large index means highly effective drug with low toxicity. (above = ?) Waldron, Chemistry of Everything,Pearson,2007, 518 ­519 Class20 6 Chemistry 83 Drug Enforcement Agency has the responsibility to protect US citizens from the misuse of all drugs. Below is their classification of drugs.! Food and Drug Administra<on has approved over 300,000 OTC and 25,000 prescrip<on drugs for legal use in the US including drugs for managing pain, hormones, bacteria, and cancer. Each these is considered briefly in this presenta<on. Suchocki,J.,”Conceptual Chemistry”, 3rd, Pearson,Boston,2007,480 ­481 Drugs approved for managing pain Drugs can moderate pain by ac<ng on origin of pain signal, the transmission of the pain signal, or percep<on of signal in brain Suchocki, Chemistry, 2nd, Benjamin, 2004, 483 Class20 7 Chemistry 83 Drugs that inhibit the origin of pain signal Aspirin fits and blocks an enzyme receptor site. It is an example of an analgesic  ­ drug that enhances the ability to tolerate pain without abolishing nerve sensa<ons. * Arachidonic acid *Natural path produces prostaglandins  ­ biochemicals that ini<ate a pain signal, inflamma<on, and fever. Suchocki, Chemistry, 2nd, Benjamin, 2004, 485 Drugs that interfere with the transmission of pain signal by nerves (anesthetic)! Enzymes acetylase! Hill/Kolb, Chemistry for Changing Times, 8th, Prentice Hall, NJ, 1998, 596! Class20 8 Chemistry 83 Synthe<c anesthe<cs are based on acetylcholine Acetylcholine Novocaine QSAR: carbonyl and subs<tuted N Cocaine Xylocaine Snyder, Extraordinary Chemistry, Wiley, NY,1992, 620 Drugs that inhibit the percep<on of pain A natural endorphin pep<de Natural agonist 3 2 1 23 1 QSAR  ­ benzene ring and N separ ­ated by 3 C atoms. Endorphins are natural donors that can occupy opiate receptors in brain so as to temporarily filter out pain signals without interfering with other sensory signals. Morphine func<ons as an agonist to an opiate receptor. Fox/Whitesell, Organic Chemistry, 2nd, Jones and BartleI,1997, 23 ­10 ­11 Class20 9 Chemistry 83 Modifica<ons of morphine Crosses blood ­brain barrier faster than morphine Snyder, Extraordinary Chemistry, Wiley, NY,1992, 611,612,618 Synthe<c endorphins are based on morphine Keep removing structural parts of the drug molecule un<l the irreducible minimum structure required for drug ac<vity is determined. A new drug can then be synthesized containing the ac<ve donor site with other func<onal groups to adjust polari<es of bonds in ac<ve site. Demerol is much less addic<ve. Schwartz et al, Chemistry in Context,Brown, IA,1994,308 Class20 10 Chemistry 83 Drugs approved for managing hormones Hormones are substances that are produced in endocrine glands, transported by blood and carry chemical signals between cells. Hormones are involved in growth, reproduction, and repair functions.! Water soluble hormones (proteins) act on receptors on surface of a cell BIOBK/BioBookENDOCR.html Class20 11 Chemistry 83 BIOBK/BioBookENDOCR.html Lipid soluble hormones (steroids) pass through the cell membrane and form a receptor ­steroid complex in cytoplasm Class20 12 Chemistry 83 Sex hormones are steroids Female Hormone Male Hormone Joesten et al, Chemistry: Impact on Society,Saunders,Phildelphia,1988, 407-408 Modifications of hormones! Female Hormone Agonist Progesterone is produced in larger amounts when pregnancy is established. This hormone prevents a second pregnancy. Norethindrone mimics progesterone. This agonist is a component of the first birth control pill called Enovid. Long-term usage (since 1960) has shown it to be relatively safe.! Hill/Kolb, Chemistry for Changing Times, 8th, Prentice Hall, NJ, 1998, 554! Class20 13 Chemistry 83 The drug, RU ­486, is an antagonist Female Hormone Abor<on Pill Progesterone also triggers the prepara<on of uterine cells for implanta<on of embryo. Large extra ring makes RU ­486 an antagonist for progesterone. Blocks the signal that a pregnancy has been established. The developing embryo is spontaneously aborted. Schwartz et al, Chemistry in Context,Brown, IA,1994,316 First drug approved for managing bacterial infec<ons  ­ an<bio<cs Metabolic Pathway in Bacteria Since humans do not synthesize folic acid, the enzyme for the synthesis of folic acid can be blocked by a drug of proper design without adverse effect on human hosts. Suchocki, Chemistry, 2nd, Benjamin, 2004, 458 Class20 14 Chemistry 83 Sulfanilamide blocks an anabolic enzyme in bacteria Medicinal chemists made 5000 modifica<ons of sulfanilamide to determine its most effec<ve form Suchocki, Chemistry, 2nd, Benjamin, 2004, 459 First drugs approved for managing cancer In WWII, discovered that mustard gas was effec<ve against cancer, but way too toxic. Modifica<on of mustard gas. Nitrogen mustards are less toxic, but s<ll reasonably effec<ve. Joesten et al, Chemistry: Impact on Society,Saunders,Phildelphia,1988, 404 Class20 15 Chemistry 83 Con<nued to modify drug and developed one that reduces nausea. Joesten et al, Chemistry: Impact on Society,Saunders,Phildelphia,1988, 404 N ­mustards hinder cell divisions N ­mustard covalently links the two strands of DNA together making it impossible for cell division to occur since DNA cannot replicate. The covalent cross ­link, ­CH2 ­CH2 ­N ­CH2  ­ CH2 ­, is represented by the black rectangle. Damage to DNA is usually repaired by enzymes, but repair enzymes are less func<on ­al in cancerous cells than normal cells. Class20 16 Chemistry 83 Medicinal drugs have contributed significantly to the increase in quan<ty and the quality of life for humans Class20 17 ...
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This note was uploaded on 10/19/2011 for the course CHEM 83 taught by Professor Bonk,j during the Fall '08 term at Duke.

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