Medchem563_Exam2_2009 - Medicinal Chemistry 563P ' 1‘ WA}...

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Unformatted text preview: Medicinal Chemistry 563P ' 1‘ WA} Hour Examination ' II. A’fl (27) March 4, 2009 III. g (26) . Write neatly. Confine your answers to the space provided. TOTAL (100) I. (26 points) A. (14 pts) 1. (8 pts) Compare and contrast the expected pharmacological properties and the therapeutic uses expected for these compounds. Provide a rationale for why these differences are expected. Indicate the biological target that is important to the effects of each. 2. (6 pts) The S-enantiomer of the zwitterionic Hl—receptor an gonist cetirizine is a more useful antihistamine than is hydroxyzine or the R—enantiomer of cetirizine. Explain, in sentences. Pb - l" /—‘\ ,H “1mg.de ijrm 4-Cl-Ph /C‘H \____/%\/\OR I z , /, cetirizine R = CHZCOO ‘9 hydroxyzine]? = CHZCHLOH mg (20%( W5 . W M d 1" All ‘ B.‘g€£27§$5) The molecular mechanisms of action of some drugs appear to be related to covalent binding to selective biochemical targets. For the following compounds, provide the following information: (a) the therapeutic use (8 words or less); (b) the biochemical target (8 words or less); (c) provide an explanation for how this irreversible process occurs, e.g., by providing a partial structure of the product of covalent binding; and ((1) account for the specificity/ selectivity of this process. 1_ OCT-33 a. (1) therapeutic use b.v(1) biochemical target 2. a. (1) therapeutic use . b. (1) biochemical target It. 11. (27 points) A. (14 pts) Draw minor modifications to the basic structure of amitriptyline, a tricyclic antidepressant, which represent: B. (2 pts) What specific advantage is there to the use of an injectable depot preparation? Longul‘ «wa pWMS ~17 remakMWq ,5? dag} #(ampll‘am/CL. Censdléibfis/ W4 0:va WMDXtOiW C. (3 pts) What are the 3C’s of tricyclic antidepressant overdo ? D. (8 pts) Many of today’s CNS agents were discovered serendipitously. From the list below, choose the one drug class that is NOT a result of serendipity and EXPLAIN FULLY how its design avoids negative characteristi®of its predecessors in that therapeutic class. Serotonin—Dopamine Antagonists ,. Benzodiazegines, Anxiolytic 5HT$ Agonists M clmo Ee‘gdslbtfl mlniloi—hfii‘s Dar HAS'A- PWssUVS ’n‘ _ me aw wwmsubte, magmas % MAD. :erNe/LS'M‘C m 6...... “PM .mcfims {Mac 244%) E 1» avm§nfv Cm VO\‘l'/V\ {an «l; " ‘ ‘ unite: bee nw enz—lwwc "Ms RSYnhs‘z‘d W\ an M , W b aqocdwts. III. (26 points) The structures below represent doxepin, a tricyclic antidepressant and tranylcypromine, an older MAOI. Tab NH!) s. H CHz-CHz —N(CH3)2 H A. (4 pts) Identify the stereoisomers that are present in each drug molecule. as and Jams eamcpm . (1315,2K. amt (92,23 «TclD (“‘7 Ms DW 0544 45 WE) B. (8 pts) Explain how each stereoisomer contributes to the overall pharmacological effect. 0% a "mm 514:.” reapfokz' H.) Mfl—DI ‘ +mms -— u. NE. NW, C.) R,€J?1'Lkl. rumba-to?" C. (6 pts) Fluoxetine: is a valuable SSRI. It contains one chiral center but is administered as a racemate. Why was development of R-fluoxetine: 1. Considered in the first place? (4) TM, iZ’chai—iw .erlnllo‘rkal a M l-CSS 2ble Ink'bvkofl My dewf‘k DB3: PMA M94 shm 1 . 4Mep'tss m, 5, mack. My: 5») +11» 4° MW 4"“ 2. Abandone53?2j)h°°+ '0 ‘ W U V‘Q‘F‘Pealfdk7, ’l’l’f' ("MMM WA cmdiWCi‘L; ‘ D. (8 pts) Identify gem forms of toxicity associated with ANY FOUR of the following CNS drugs which limits their use or has resulted in their withdrawal. a) Remoxipride A“)th Wra b) Sertindole armqmfiafio‘,‘ I WNW—{ct l7 ' c) Nefazodone LN‘U— C: H I d) Nomifensine Hwflflfic WA e) Clozapine 4W0 lockllosi g 5 IV. (21 points) W Al. £6 gts) The structure—activity relationships for the anxiolytic 1,4-benzodiazepines are well defined. t types of substituents at R1, R2 and R3 are required for activity or to enhance potency? R1 0 '2‘ " “ cub.) Wraitth c mow mac: w e \Ou-¥ “(it egga.4~\\lh K \ \ f—— w i.“ l N‘§ , ‘ qulq Aftg $b»§>$ ?V€—§EA~. came a“ 4thfipqaima“& - R? Y exam w¥~ 32 P5 , {Dc-Wee gtficfia. 2,3“ "icbifie “*3 “’f) EV‘K93 l £4}de LL 'Pfi‘m“ IA {pa-FE Aglks‘awk {dawn-3‘ 3;. (fin-“*3 ‘5 mf‘Mu'f: ES —" Enjés wkw. u LL. ‘ F634 taut. :5 F B. (9 pts) Chlorazepate is a pro—drug. Provide a scheme that explains how it is converted to its active form. Be sure to show all intermediates and final product. Draw an arrow pushing mechanism for the . . 03m “’— 1rrevers1ble step. ‘ m, “A ‘éowa ,..\ ‘ d 7a 0";- . (O H H OH U Q i A I J Kw" Q A i. N / \ \ i *m-\ K"; » kj 2C7} r- M rm \h\ N ...._;wu \ ‘ 0 if “A C“, 03 my» \A; ,Mi\ M MN‘F’ C1 _ N H 435m c) 0. 'Pk 0 g m «LAVA. ‘CM’ N _ -Coa l trre Je L‘WDLQ 0 * .. u ' (fifflér "q, L: l ‘x‘\ N ' ‘ l 4-, a \/M“ H H w» ‘ 7 7 cw. N C7,?” at... 5' n F a Mafia"; PA )‘C. (6 pts) For the drug molecule shown below identlfy: Owe“ iad,‘ a Q S.» g a“, .QVM‘ 0-0 moraiazezsgam \ I V (i) biological target (ii) mode of action at this target , fl (CL’LQT‘W‘: C . i? .M . . . CH‘ ~LL~AW a :5. macaw (in) precautions assomated With its clinical use W ‘ W: \ 3 ___ . ,. u s. x a- a p (Hagar, m .flwww. . .4 75 “I c, N a K M / z ‘ ~ \ N o v « xii .3") F / E_O_C2HS I ' ’h “whys”: cat. , E N _ . _ s. ‘7‘ 1 J , 3‘7 *2 “V7 { Flow/M ZEM—A‘ as; is.» aégacx‘n4w~ V ‘T,’ LY; F N\CH web-Ha. \owézfii‘fi a? ‘94. furs—.{zufi Q' , . - :5 O 3 “-->: amauaxalm . s? e» «at «Ami (M ; We 0 g ' . ‘ a :Y j 75 \J n. 153% e i Mbél Raw .5“. icy-wad" xvn. Par: n a»; S 43153.? GiG-SL f3; ,r'f ~le WA : A: Wfiu-fi—ffi; wit p dachost; ...
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Medchem563_Exam2_2009 - Medicinal Chemistry 563P ' 1‘ WA}...

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