Medchem563_Exam2_2007 - Medicinal Chemistry 403...

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Unformatted text preview: Medicinal Chemistry 403 I. (/0 "V (26) Hour Examination II. (22) February 28, 2007 ‘ III. (22) W. M (14) v. NH (16) Write neatly. Confine your answers to the space provided. TOTAL (100) l. (26 points) A. (8 points) For each of the following compounds provide information about the biochemical target and possible therapeutic use, with rationale based on the mechanism of action of the compound. Where possible non-reversible chemical events account for how the drug produces its effects, provide chemical structures that account for the process. 1. N02 Tag mm, WM z) amwm £7” HO O 0 H3 marriage/Marrer . WWW“ W“ HO ‘ WW WML‘DmO/é . r a, ' ' MWeWnWtWW 7” w WW ‘ \EUE/t( B. (8 points) For he following compounds indicate the expected pharmacological activity of each and potential therapeutic use. Explain what differences would be expected and why. C1 C1 O CH3 0 / \+/H (a CH ~CH2CH2N: and CH—N N—CH2CHZOCH2C —o * CI: CH3 t gab 7L gWW a“ C. (10 points) 1. Agents that interact with MAO—B centrally are thought to be useful drugs. Explain. Specific rationale, uses and effects are expected. Confine your answer to the space provided in 50 words or ess. - x \ ~ mm M WJWW M mama/44 M4057; W / K . c%wdxfiudiln.% fit & wiKQAM4&QM2ZZ£ g lg’QWQfl“j%MZMM W @JWWWZJA ,MMaWW fimwwww» 2. Thoroughly explain in words Why proton pump inhibitors, like omeprazole, rabeprazole, etc, have pharmacological effects that last many times longer than their plasma half—lives, 30 words maximum. OCH3 11. (22 {YES} 00 l " (CH2)3 —N(CH3)2 NO R-GROUPS (14 pts) Draw minor modifications to the basic structure of imipramine, a mixed SHT/NE reuptake inhibitor, which represent: 1) a metabolite with increased selectivity 2) a high potency phenothiazine for inhibition of NE reuptake _J antipsychotic ./ ' i / N /\\/ Cl 1 / Pr l / \ i. or as -w W it or w N N“Cl 3) A low potency thioxanthene antipsychotic ‘4 4) An inactive geometric isomer of 3) C15 ..., is a ‘ ii'fr’f’jj) W for r /‘\~,m \ \Gl “xi/sci ayia‘fa CW V §fi,»‘\/ L, H cit» é /<:‘\t+ \ ‘W W... N“ HM” CH2 CH2 N\CH CM; 2 w (8 pts) Newer antipsychotic drugs have minimized EPS (extra~pyramidal syndrome) liability and somewhat different mechanisms of action from the classical antipsychotics. However, the toxicity issue has not been completely resolved. For the two newer atypicals listed below indicate; a) how their neurotransmitter specificity differs from the classical antipsychotics b) what (serious) toxicity can be associated with their use. Remoxipride l l m it) l C blflg‘fpv gig C“ aplqsfifi. mWffi» Ziprasidone Semicfiyfl PRES WWiM waittgfiwl $1. imam»di [CWimle /{l‘6w~l III. (22 pts) Monoamine oxidase (MAO) typically acts on biogenic amines, but occasionally some drug molecules are also targets for the enzyme if they contain structural elements that mimic central neurotransmitters. a) (3 pts) Citalopram is a substrate for MAO. Based on your knowledge of the type of reaction catalyzed by MAO, draw the structure of an end—point metabolic product that you would expect from MAO’s metabolism of Citalopram. mimim‘w \‘\,/..M'w”r~ .“WNNN ) "N , ,mfl,‘m.«....._.w. NC 0 CH3 NE a ' i NW / O x"; WM”?£Q\CA®L‘WA‘§ My”? GDZH l deaka m:me ‘ (5* “a... “N” b) (3 pts)@rcl/efthe structural characteristics of Citalopram that most closely mimics a central neurotransmitter. Name that neurotransmitter. m 50mm (new 5mm) 0) (4 pts) Citalopram is now the most widely prescribed SSRI in the US, replacing the first drug in this class, fluoxetine. Compared to fluoxetine, what are two positive attributes of Citalopram that can make it relatively easier to use in depressed patients? (3+ W is, a Wflwk-flr (j‘t’PZMwWWOiN 6% $3 My Mb ‘WWS GM 1% WE KMQL ‘11? if?) 5WI+CLN 6‘), active WM (Pius shmsfli) mama» east MWWM. d) (4 pts) Fill in the blanks. Phenelzine and tranylcypromine exert their pharmacoloog ical activity through WW...” Sui a; $1» inhibition of MAO- awwjb i m—EthsmwbaMcf) e) (8 pts) Moclobemide is the first in a new class of antidepressants. 1) How does its mechanism of action differ from phenelzrne and tranylcypromine. Fl g Rim/<3 Muiblgwids lg at redergiioifi mkibiM‘fig MM)"; / 49”?) W Simian? dmgfl ma {FTC—ffirsdoie mixtihéws % Hwy—Fit amt M ii) What advantages(s) are expected over the older MAOIs as a consequence? bacmw, @‘f‘Z‘lm iv. e we ’ * ohm» (I ewfiw ‘5» “a”. PM mpg X “My” '3an WW mama. Tia-e Hddfiibié iaiqlbfvtw cflnwéag Mm. X/ "‘“\.t\, ff “We; Mac-Rm 6?: agafl WM M @kaet _“ xvi/€— ” 19% «m autism Csliengcfir Wins tr?) aflfifi WWW mfiiflwg g if comma, WW mmlsis§¢L«gi¢- mews. émdebttnsv *9 Mam W ' IV. (14 pts) H O A w; I I l/‘AN" f “(2 R: m ‘ {MN} Kl“ (a i F j: ,4 3%») t 9 l 2 w r n.” N ' ML " Hw/ Waf: 5 «C‘ A? Cl _ N COZK “Aka O B The two benzodiazepines A and B above are converted in the body to a common active metabolite C that is responsible for the majority of their therapeutic effect. t: 492 a) (5 pts) Identify C. Is it formed enzymatically or non—enzymatically from A? From B? 6"”; Met *7“ [I C is floc~éliqze.3?<tm, $102M QWZYMKHCMW 940M A) (XML “0‘”' 7 ’2 3»? 0M a) (7 pts) Draw an arrow pushing mechanism for formation of C from either A or B. Be sure to show all intermediates and final product. 0) (2 pts) C is not a drug in its own right, but is converted to another active metabolite that is used directly as a therapeutic agent. Name that drug. (53); Ct "Le FR M ll (t. V. (16 pts) For each of the terms listed below define the term in light of its relevance to drugs that act on the central nervous system. Serendi it define and oive two Good exam les of it for CNS druos ‘ ye "1/in é (“:12 his” by W‘MT k 0 “E CL C» C “Jeri/1h”; 0i recovers Sémeé'lmvtfl ‘I 6‘ 5-P{(IC‘L \lkj vokfie lagumfi «(436‘ $0M€§~K3wfl €15,ve Daiqvvecfl QJUW;1:$’O W,’ V r V V - fit I \ «fl ’v"), Pa 5“ ‘ ’l vl—ctle a?»va ‘CU’55* (mime ti b Horace e «Maya } K" :tsg,.y \ a talehg ewe-kg 04$— LsD c logP V I 7 "We. L‘ «induct—st}; 16:3 QQ'rXVTfiFTf-‘A (we, @Q‘tCNM} A Mausem‘e a? lilpcrplrmgulfl . 1pm. “'59-: ‘r- :‘OA 91 0i {My be have at A u”) TML ?CU‘\—R\~Tbi\ COE‘WFCQJH' LS ‘3!”‘f\€,, 00" 0‘»? “V‘JQI [M50LC{“(¥ 52(3wgnol) ‘QOCi “ {artikrv \um t. r“. 6,7 ‘9‘ cf ‘03 Mag mm Vvt 01,3 l" b’k [lg 35 +t‘ckv‘ Egp :chfilytoeralem \‘s a. main/thee c9?» «we, ft%(/g gammy; mi" ¥fa,,vtbpc=€’l'$>f0}—QM$O Ix" €'§§\uqtg§ a» wrote chfiaX-g Q‘s-g; k7 au (1: Pkg big, avid (Calm {tic mole (’méj‘éi 6(&\~ cs Sb lb QLQLL n L: \Y‘\’\€ \O Dert preparation V M oth 91: c rd» $0.81 a; S: Ct. ole“ v1.3 ‘0 y “51 5‘41“ ' CL Sail-3 0.41105 .5 Wok as, V\quvxc‘?<:, Cleaves/“WM , 0““ dcfo l5 diagolvm‘ l“ (L VG’WMEM’ all (Md ffigcci‘ffin {lacw’llo mfid if S 5 '9 w; {‘6‘ L“&€€£ CLNL “Ck-pic“; Myfimhyzciir ‘j—$H:X‘ti i as}; §~LL ' (07:74 Pl?“ ILL (3“ {‘83 our? 3 TM“; “HM/J3 once (,1 “lease: (or less) 6103'031 l" P / (Milk? 0: in CERF ?C‘a_t‘l”i{( glen" YFQ ‘3 l6 rm tL (W M? .9“? ft #41361 C tn (12%;, 033mm 03} a: m 0H 1; ("UMP by \P a \w; I 'lmfll QCC’CF, ‘T’kefl I ESLLECVLL§~CLVX (Dwell-S of“ plasma e——c.-}<mwg_ tuHTc C01“ 5 ...
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