Chapter 10ManipulatingMoleculesandDesigningDrugsMonday, 28 September 2009ReadingsChapter 10.3 – 10.4Homework: Questions 15-22, 37-40Functional groups play a role in _________, animportant consideration for uptake, rate ofreaction and residence time of drugs in the body“Like dissolves like”Polar molecules have a nonsymmetrical ______ distribution,leading to the build-up of _______ +ve and –ve charges, !+, !–Polarity withONIncreases______solubilityCompounds that do not contain many functional groupsare typically ___________.E.g., _________This leads to insolubility in water and accumulation in cellmembranes and fatty tissues, which are largely hydrocarbonand nonpolar, i.e., _________.Solubility properties lie on a _____________Water solubility can be __________ by protonation with H+.Compounds containing functional groups that are alkali, or basic, and when the basicity is conferred by a nitrogen, e.g., ______, are called the ____________ form.The ________ can be converted into the ____ by an acid/basereaction.NCH3HCH3OHH ClNCH3HCH3OHH+Cl–Pseudoephredrine(_________)Pseudoephredrinehydrochloride _____NCH3HCH3OHH+Cl–The resulting positive charge on ____is balanced by the chloride, Cl–, ion.This is an _______ compound, e.g., NaCl, common table salt.The ___ form is preferable as a drug because it is more stable,has less odor and is _______ soluble.About half of the drugs are used as salts.Note: revert back to freebase by treating with base, e.g., NaOH.Drugs with similar physiological properties often have similarmolecular structures and include the same functional groups._______+_____functionalgroups10.4 How Aspirin Works: Relating MolecularStructure to ActivityUnderstanding the action of aspirin, requires a look at the body!s chemical communication system –"_______________The nervous system relies upon the transmission of electrical impulses but hormones are released as _________ messengers that travel through the __________ where they can be circulated to the appropriate body cells.Hormones –!More DetailsHormones are made in the body!s __________ glands Hormones perform a wide range of ________ and thereforedisplay a wide variability in structure (functional groups & shape)Thyroxine –"secreted from thyroid gland, regulates metabolismInsulin –"secreted from pancreas, regulates _______ usagefor the body!s energy needs. Diabetics have daily injectionsof insulin, a small protein of ___ amino acids.Richard DiMarchi, played a role in diabetics research.Adrenaline –"a small molecule for “fight or flight” responseSteriods –"influence sexual development through adolescencePhysiologically active drugs, like aspirin, butwhich are not antiinfectious agents, invariablyalter the __________ communications systemWhat does this mean?The system is complex therefore ________ messages can bealtered at the same timee.g., aspirin reduces ______ in the brain, relieves ___________ in the muscles and joints and, lowers the chances of heart attacks.OHOOO CH3AspirinThe versatility of aspirin and other nonsteroidalantiinflammatory drugs (NSAIDs) is related totheir ability to _______ the actions of other molecules.e.g., one way aspirin operates is to block cyclooxygenase (_____) enzymes.Enzymes are proteins that act as ______ to increase the _____or selectivity of certain (bio)chemical ________COX leads to prostaglandin production, which in turn causefever, swelling, pain sensitivity and others… by preventing COXaspirin reduces fever and swelling!OHOOO CH3Crystal structure of the enzyme COX-1 with _________ boundThe ibuprofen binds to the COX-1 enzyme and acts like a 1-nm “_______ in the works”, or a ________!HOOAngle-drawingof ibuprofen3D representationof ibuprofenExpanded view of COX-boundibuprofen with hydrogens removed for clarityAnother way aspirin works is to suppress pain receptors, thereby relieving pain.OHOOO CH3The benzene ring allows __________and aspirin is taken up into the cellmembranes of specialized cells.These cells are then blocked from ___________ inflammationSpike MogwaivsNSAIDs exhibit their effects to varying degreesAcetominophen blocks COX but ______________specialized cells ==> lowers fever but not inflammationHOHN CH3OOHOIbuprofen is a ______ enzyme blocker and specializedcell inhibitor than aspirinWith fewer functional groups, ibuprofen is _________soluble than aspirin with five to 50x ______ antiinflammation activity and fewer __________OHOOO CH3Aspirin is unique in also being ananticoagulant of bloodRecent research showed that COX-2 makes prostaglandins but COX-1 regulateskidney functionOur three NAIDs block both COXs, i.e., they are not selectiveResearch developed new COX-2 targeting drugs –"___________But, proved to be no moreeffective than NAIDs. Ultimately, Merck withdrawVioxx due to increased riskof heart attacks… but still,both drugs were “___________”stimulated by direct-to-________marketing.Structure of COX-2Final comments on NAIDsWhile the chemical structure of aspirin doesn!t change________ aspirin tablets are the same.Inert fillers and bonding agentsCoatings to keep aspirin from beingreleased until it enters the intestineBuffered aspirin has weak bases to actagainst the acidic natureThese differences in formulation alter rate of uptake and so, how fast it acts and the extent of stomach irritation.OHOOO CH3OOHOHOverview10.5 Modern Drug DesignPenicillin is another famous example from “_______” sourcesAccidentally discovered by British bacteriologist, Alexander FlemingHe observed that the area contaminatedby the mold Penicillium notatum was____ of bacteria.He correctly concluded that the ____ gave off a substance that _______bacterial growthLouis Pasteur, “In the fields of observation, chance favors only the ________ mind.”Going from discovery to pharmacy was not easy______ Separate _____ ConcentrateAlso, the efficacy of the drug in humans had to be ________.WWII drove a lot of this research and development and therefore many lives were saved then and since.Benzylpenicillin, a modified form ofpenicillin is another _____ moleculeE. Coli~2 µm~1 nmFrom discovery to systematic researchSmall changes were made tothe _______ and the ______tested.As with NSAIDs, optimize ______ and _______ side effectsThere are more than 10 next-generation penicillins in useBacteria develop resistance by secreting an _____ that destroys the penicillin structure before it can act. Newer drugs differ in bacterial specificity and susceptibility to