Medchem563_Final_2008 - Medicinal Chemistry 403—502 1....

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Unformatted text preview: Medicinal Chemistry 403—502 1. Wk} (12) Final Examination 11. w kl (18) March 19, 2008 p 111. M6 (16) Write neatly. Confine your answers to the space provided. I. (12 points). Charged molecules provide both challenges and opportunities to obtain selective agents. Their utility depends on their biological targets (sites of action) and on selected routes of administration. For each of the following three compounds: 1.‘ Provide the pharmacological activity and therapeutic use (10 word maximum) and 2. An explanation for the selectivity of its effects based on its charged nature and route of administration (15 words or less), in a complete sentence. 131:3 Br- activity/use. ( '- ’ i H3C’ .. 03$ 98 _ _ W 0 fi m [A12(OH)5]8 activity/use _ . 5; 5; Al, WWW ‘ H O _ W CuuN NI-CH CH OCH C—O . \ \_/+ 2 2 2 I a u a I II. (1 8 points) A. (8) Esters are important derivatives of drug molecules in various therapeutic categories. For each of the following two agents: 1. Provide its pharmacological activity and therapeutic use (10 word maximum) and 2. Explain why the ester is important to the therapeutic use of the agent (vs. the corresponding non-ester). H3C‘ 9 p1 —C-0 H 01-1 activity/use Hac 1 DC. H3C\ (IHzNH-C(CH3)3 N-g-O H3C O activity/use O OH II I ' f “441m H3CO-C-CH2CH2QOCHz-CIH-CH2NHCH(CH3)2 flaw/744x . . M 5W”? WW ~ mafia/W WMWWWW B. (10) Some compounds produce their effects by reacting chemically with biological targets that are related to their activity. For the following compounds: 1. indicate What is the compound used for therapeutically (5 word maximum), 2. indicate its biological target (8 word maximum) and 3. provide a rational chemical mechanism to account for its effects. 0 m HBCHZCONIJ s CH -CH It} CH ~‘ N-CHz—CECH , 2 2 ( 3)3 H - I—l H3CH2CO 1 use/target E p I use/target ? W WWW (W MNWMLWA 0 SAW ——————'—Fr l-l- , a as 4. K— tag—c204 2 R»N:;-r3Hfic=cH RAMP»: A 4913: BM :— 0 “(a “F‘ v {'5 1 4‘ M 8” FM A120) 4&0. ‘f' 6’ wt" P R ‘l‘ H” E-N’C/45C:C<g III. (1 6 points) A. (6) Provide the expected therapeutic use of this pair of compounds (8 word maximum). Explain in one sentence how each of the compounds exerts its affects (mechanism of action), including the expected biological target for each. How are these targets related to the desired pharmacological effects? H No2 \ I H3C\ A E INCHz CH2‘S-CH2_CI'[2'NH'C‘NHCH3 o H3C WWW The F Wm #14 rue/#wa ’ WM W A 5 M H7<+Aa7FW B. (10) Provide the expected therapeutic use and the expected biological target for this pair of compounds. In one sentence explain how each. of the compounds exerts its affects (mechanism of action). For each write a rational biochemical mechanism for the process that is the major route of metabolism. O 0 II II + + H3CO 2 Br- (CH3)3N—CH2CH2-O -C-CH2CH2C-O-CH2CH2N(CH3)3 CH oN/ 3 E ZBr I, H3CO “'CHZ-CHZ- -O-CH2—CH2 H2 é- CO H2 Use/targ P a} dot H3coj: _ 2 w, a w a r w” H l»: v“? ‘3 , C, x 4/ ) p ’0 ‘ C /~Ir,46W‘o H OJ cl 4‘ t h } 60,2444,» H «‘5 (Macaw l W W i590 (i /Ml3 0/ //’\ / 145" + “3/ (ll IV. (30 pts) A. Draw minor modifications to the structures of phenobarbital and carbamazepine (shown below) that satisfy the following criteria. No R groups. (21 pts) J: 0" NH: i. A diphenylhydantoin that causes gingival ii. The sodium salt of i. for use by injection. hyperplasia. \ 0 o -' K a V A) N l \ \‘w— </(_\ H409” g9 Fasplofiilq/l Q \+ N40 0 K \+ —+eo . iii. An i/v anesthetic thiobarbiturate. iv. Phenylethylmalonamide — an active metabolite of p \ ISL phenobarbital. O \ \ E+ \ a” N “L — M 1+ l)“ // {i P b / / L O o adverse side-effects. Show stereochemistry. 0 “JD JDH" / firms mla‘fil 1T \ \ N i \ C-.D N H“ L B. Provide an arrow-pushing mechanism for the conversion of v. to Vi. What enzyme catal es this process? (5 PtS) EDP H D ) fl' “‘47 H "l D prfloLL hjaoqsfl C. Explain why you might treat a barbiturate overdose with sodium bicarbonate (4 pts). NQWUO; aLkoQiVUZQ 'HFQ, (nbmcfl7> aciou‘c UMA-Q/ 50 Marc okam Mom-wig In ‘J‘Le Kidnej +obo\{_ \s lsmleol m less l$ recMS‘b-I’LG-Qd. This prev/1846; reimL Mead. v. “fists A. Chloral hydrate was introduced as a hypnotic agent 150 years ago and is an example of one of the earliest prodrugs. In the sequence below, identify A, B and C. What type of metabolic reaction is involved in the conversion of B to C? (8 pts) KEdMIJl‘iS/l lq " _HZO ,0 /OH _A 47 // age—CH B _—> C E7 ” C‘gc- ” C'\ H \ +A Lohlemv\ OH B. Ramelteon and eszopiclone are two of the newest prescription sleep-aids. (i) With which central receptors do they interact? (Be specific!) (4 pts) RameL-l-eem. - MT! 1 MTZ. WW; . I Es;a‘oic\0nt *‘ o<i~mintn:n smear/n+5 (ii) Ramelteon is an analog of which sleep-inducing horm ne? (2 pts) M43 W9“? A C. Suggest specific benzodiazepines for use in i) the elderly; ii) patients with liver disease. Justify your choice in each case. (6 pts) QTMazOla/M warez rts shwe numb Magma“ Minimizasi \hwfioud“ .efi-eci-S M m retolwflj. ff “ L Loflaz am szM/a—L H" Cam lag—lac!ch ‘7 VI (iSpts) 2.01/12?! oL anti: «ex/(ami—COLl 53mg.— uai wing W/‘L . ‘5Pwot' m mid obvsfiwfin. A. You are a clinical pharmacist working with a neurology service. Because of the complex nature of drug interactions that can occur with the treatment of seizure disorders, the neurologist has asked for your advice when making the following medication changes. (i) (3 pts) A patient is currently taking lamotrigine, and will be started on phenytoin. The dose of 1amotrigine should be (circle one): @) Decreased Unchanged WhY? LQMOhI‘jflQ/ 55 Make/teal 00(qu MMIW N/gl/MOMWm‘oiq/fi‘on. {’vm (QM Uéy‘f And Wm I‘M” 543 MM)“ (J/ ’00,). So mowz. (Amohfi'hé WM lee, needed «farm same ’tkvaym ii) (4 pts) Apatient is currently taking carbamazepine, and will be started on felbamate. The dose of carbamazepine should be (circle one): Increased Decreased m Why? arlamamn‘necoez) .5 mwlouwl b3 CTN/w t9 CBzrepop‘a/Q,Bo% 092 owl Ofli’Q/fofi‘d‘e Wt amt/t tkvafw‘wwj. Pelican/mic MW OYPZALP AM So moi/«w» 08$ Ln?! IMWS?» wi'epofiv’c. 'Tkaefvm, no dose 0141);»th .‘5 \ new. [9,“; ‘tOK'ih/tflg Wm cm kW wszom‘de to me- B. Felbamate is an infrequently used anticonvulsant due to severe toxicities that arise with its use drug. (i) Name any one of these severe toxicities. (2 pts) aptam‘o anemu‘a , hepavho foxu‘ Felbamate is metabolized via hydrolysis to product (A), subsequent oxidation to product (B), which then is converted to a reactive, conjugated species C, that may be the toxic metabolite. (ii) Draw A, B and C and provide an arrow-pushing mechanism for formation of C. (9 pts) O H" o H N )L O 0 JL NH 2 K 2 hydrolysis o —-—-———> H 0 Felbamate v11. (26 pts) A. (8 pts) Methohexital is an ultra short-acting i/V anesthetic which is M a thiobarbiturate. Explain fully how its structural features contribute to its rapid onset of action relative to the sedative—hypnotic barbiturates. Coward wH—k Sevikhl/‘C'Wlhofi‘l/ LarLrt-wmu, L0 H\ CO meflohwi‘ta/L Lab mow carbon Load H30\ ; C—CECCtHZCHa I“ N M C 50 mtva L ex (w t» . A CH2CH=CH2 5) W? 3/4 a}? O 3N 4 O (9 both Mrhn clowns M C5 are WISa/Mmfed, H what/l» Mso [WWI/85 fin Ayopkxbm‘xj of It- ‘ (A‘ 0 Lu‘c'u go, Infinite/WW to”! 1% GAG mMK/x hflp'b“? ULMQ‘iU (R5 I {7] am m are WM‘O‘I " B. The imidazole and diazepine rings of midazolam are critical to the formulation of the drug for i/V administration. (i) Place an A inside the diazepine ring and a B inside the imidazole ring (2 pts). (ii) What property of the iml‘olaaola ring helps formulate the drug for i/V injection? (2 pts). lmr‘dflzolez W3? 0% lactate wwl (an qty/m gavbf «fun/m at or below pH 55 (iii) What property 0 the diazepine ring helps formulate the drug for i/V injection (4 pts)? Dmaepil-Q, aim rf'flm rlYH--0r€/fle9( form ail” 3'5, (A)th has good (MW SotvtL'vaj (iv) Draw the structure of the water-soluble salt form of the drug that is used for injection (4 pts). H CH3 , /,V+ 01 Yg/ “3‘5 N 0 A m “'3 or Cl -N cl (5:7? 0 F O C. (6 pts) For each of the following i/V anesthetic drugs, identify their receptor target and mechanism by which their pharmacological effect is terminated. ’ pH 3.3 Target receptfl Mechanism b which action is terminated Remifentanil M ,0 PM A Yew/{*0 f la ‘6 m Ketamine N M DA Yaep‘l’v'r Yafle'fé {Yt ‘lawh‘on Thiopental EVAQA receptor M‘é’l‘fl‘lywh'on ...
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This note was uploaded on 01/31/2010 for the course MEDCH 563 taught by Professor Wendell during the Spring '10 term at University of Washington.

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Medchem563_Final_2008 - Medicinal Chemistry 403—502 1....

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