problem_set_2_key - MedChem S63P ‘ Conference Sections:...

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Unformatted text preview: MedChem S63P ‘ Conference Sections: Winter Quarter 2009 Tu 10:30-11:20 T473 Th 9:30-10:20 T625 Problem Set # 2 1. Organophosphorous anti-AChE inhibitors can be extremely potent compounds due to their ability to form stable phosphoesters with a particular serine residue within the enzyme active site. Although most are classified as “irreversible” inhibitors of AChE, certain oxime~ containing compounds can regenerate the functional enzyme reliably in vivo. Rationalize this mechanistically using the compound below. What are some limitations of these compounds? F ' ““1 ‘ ’ ‘ t ‘ ‘ y»; > is ‘(se thdnmue (“mimetic {3-}??th emwmmmmmw «Wt ‘ _ $7 AFR“ Z»P§”tf¥(illl€ attioxime methyl chloride fig .3 Nita“ {if m a t e123; "““’*~- x” S“ * “fi‘k‘efiix :gMM,tMMA3\ fixx ~j {new} .v‘” a; “ 9.. a W "“ “I'M x3; é;th “‘u ,1 M, t teasers.“ fife”, t w.» In“, a» a»? 3%" A? \ «i I ’ ,V ., wit;¢fl$t5r§$ Wm‘KmA-m. mew—<4! L MM L '6‘ m g N x a i i ,tfij’k Katha» r3; Mil/>3 gikmx 4:1, {h gekfih gr” 5:; “x V _ V 911% , $3»: gm ‘ x k E i ; £333 “3mm Wfiwfi; 9:33;"? “Ce: hawk“ E R13 x t i ’ ix. , f; 9“; $23 53% $3M W'fiwx, :5” Rim 3 i is: wu- figs t \§ i 1W, 2 i k “x a :1 E 9-; in x :‘ vi; “~32 enzzfifizemk ~95, a.“ "CELS kflfie‘fla J‘ N _ : cw; m w b) ff“ ‘lwfll \ _‘ \ _ t w o. a a m @ Rwrwm we, Em... .. ‘3 \ m‘c‘ixjamt was, *m“§&.’s t - MedChem 563P Conference Sections: Winter Quarter 2009 Tu 10:30-11:20 T473 Th 9:30—10:20 T625 Problem Set # 2 2. (a) Both Atropine and Scopolamine are muscarinic antagonists that block the action of gm”- m.mimi.u-v«. ACh at post—ganglionic cholinergic receptors. Identify the key structural elements that contribute to their recognition at these receptor types. In addition, rationalize the large difference in pKa between the two molecules. Which compound is more likely to exhibit CNS effects? Why? 5 Fa if“. - " ’ . ‘ t Ati‘egiiine {Raceme Hymayauflnc) pig: )M Scopelamixw (:3th Hiypsine piiia : "31> "05M \ ,sz (b) Identify all chiral centers; lis the ‘ § “43: , " K" ‘ ‘ K r ‘ #1 k a ‘k fl ‘0 a» J mam” #1 “3 3L :2; a a} LAMA 4: 5.7:? <3?" ‘ “if: fiww ‘33“ L «M a $55 » «fig anfi “7132:: m "A M”><=C"“ hava «5‘ ka‘gr‘ KT“? . kw} w”, (i; p A g r a ‘ ‘ ‘ i 0 W41, £2 «:fiv fi Wm jaw: f C W52 «K i’ (an “3% ‘Q "g? L?” “a w? w "’ ""-~I—‘x3 \ w... I! a m. M {Ma W L (“Em K ins” Q t W W ‘ ‘V w I. ~—' «a; ,c - ; u k. f5 .9 a "a: ‘ ' 1 “’ R Ck . \ C,» if) i. mm. ‘M - “’1‘ '~ ‘25. g 35f}. "f V3 t «Elma» J éfiwwwggtw vi, a, 2 £5 “WI mm“ (3“ ML MedChem 563P Conference Sections: Winter Quarter 2009 Tu 10:30—11:20 T473 Th 9:30~10:20 T625 Problem Set # 2 3. Identify the general SARs for the antimuscarinic compounds below and illustrate key features of each that fit this model. ‘ \a. :O AAJmW-W‘” “(F Hi 3 H > I I + I C~O “CH1'L‘HI; “N"1Pl‘ j - r z r , i - l a . \‘ iPL‘ / Til \ W N y/ B1" \“*~ -/"Gi}’{3i{)1)y1‘1'913It? Tiotropium {Spiriva'j v I / mommhehm [Rolmmll aerosol used in chrome obstructive [profimmmew pulmonary (118262156 ’ ‘ E t L“ ”~ haw lgéi t. WM» if L 1 ~' ‘ ch‘ec.ofV “ 2‘ is git}; “123% “Mada 231m m a, Q, MedChem S63P Conference Sections: Winter Quarter 2009 Tu 1023041220 T473 Th 93040220 T625 Problem Set # 2 4. Briefly discuss the pharmacological activity of the compounds and s in? 2" ‘ , Kay» uses for each. I V , _ x I {35%.gmflxa ’4, fl. “1413; xx...“ g frag-mg "if: (‘3; 5. Describe the two main classes of neuromuscular blocking agents and how they differ. Define the SAR using any neuromuscular blocking agents shown in 4. MedChem 563P Conference Sections: Winter Quarter 2009 Tu 10:30-11:20 T473 Th 9:30-10:20 T625 Problem Set # 2 6. (a) Write a detailed biosynthetic pathway for the synthesis of Norepinephrine from the amino acid L—tyrosine. Be sure to include a mechanism (including all intermediates and enzyme co—factors) for an important decarboxylation step during the biosynthesis. , w (3H CH GOSH , ' HO, M CH 'CT'H-Sfiftin “‘ “ Ncn‘epilnspinim \ ":1? ymaé era. mm MedChem 563P Conference Sections: Winter Quarter 2009 Tu 10:30-11:20 T473 Th 9:30—10:20 T625 Problem Set # 2 (b) Outline the various metabolic transformations that epinephrine/norepinephrine are known to undergo. Write mechanisms to account for their formation. Mem‘mhmn QH ; OH HQK AX ,CH-CHMIR OH O aldehyde Hot a T )( V5” ‘7” ‘ MAO L {E (lichydrogc1lasc “*‘V “ft/{’H CC )H is ,9, kL’H—(‘iH y ,Lr Ho” ~ — H0” l j CQMT 3A-dihydroxyallamielic acid loom“ QH OH Haifa am ,(ZTH'CTHaNHR ‘ N ‘1 e tr, s ‘ 1E0 WW» / (H c. OOH HO/JQQXL? aldehyde (iehycimgenase L 40% 40% R : H Norme‘ianephrine c m 3-111‘3111‘S’Xth’hymoxy R : CH; Memneplu'ine " ~ .\ XMAS mandate and than rcductionw “ “ m OH HACO\ CHCEHZOH ' ii H;C‘€3\ ,§;:‘-»\ ~/""""-T:,,4/ 0’ 1 f0 If _ H0 7.109% {‘2 g i / EX 7 t r c , } )C)’“S‘”” 0’ ‘V 5“ mm 3~1116t110X}'—4hydroxyphenylgiyco} b H icons/ax a “ i’ , , HQOQ O W K Ofig}:zcuroxndaimu H0” K Ox «so» HOStx"/‘{“~-~Tzv/ OH OH H OH OH 7 OH ../"“‘+ 1+ 7 ' E . + efl‘ g / itw Hat) :_ _ 1 MAO AI CH CHqNR 3» AI‘C‘H CH NR —» Am‘fi (TH-2V RH” m» CH CH x R H H O OH in —> RH) (FIB e» RH: H + H202; i QH 11E 1 AICH CH O 21 (a 13m: , / (lehytogenase (9H 0 H70 OHaJIJH (PH 9 AICHWCH «F ArC‘H (it-170}; new» AIC‘H (:1 OH H " NAD+ NADH MedChem 563P Conference Sections: Winter Quarter 2009 Tu 10:30~11:20 T473 Th 9:30—10:20 T625 Problem Set # 2 7. Shown below are compounds containing adrenergic activity. identify the route of activity (indirect, direct, or mixed). List some common therapeutic uses of each. Are any of the ' agents selective (i.e. Bl or [32 selective)? Can you identify any prodrugs? i {iii X :2; {TH rm (TH: citywide}?{*Hyt‘i-ig y}""’”““(?1‘”1“£ngEHR R {Bu ‘ my ‘ ‘ ‘ (in, {tigfx‘iit‘iti‘ii,“ moctg ii + (g m 5:;fifting:i‘tfiflfi: W); fig. 9;} ENLSQ MedChem 563P Conference Sections: Winter Quarter 2009 Tu 10:30-11:20 T473 Th 9:30—10:20 T625 Problem Set # 2 8. Discuss the SAR associated with direct acting adrenergic agonists ix Ali contain pimiciriiyiamine structure. Aromatic: ring: pi‘ienyik few others are effective 3‘ AH cozitzzm one or more aroiimiic hydroxyi groups a. At (,zrrecept’zin‘s zzszJH, 2* 3,2431% by {“(L if: fold but siiii 20 times less than Some reimiveiy selective: [tingcmists hear me MEMO” groups. is. Iv?6:2:my:suifoummcio an acidic group iike a phenoL may be snbstitmed for the 130% in a catechol dcrivnti‘ve but not at; the pwpositioni This; change. can he mack“ to eiiilzephriim 11.01%}?illfifihk’ilifif and to isopmtemioi. c, Other p913? grzmps have also relyiaced the MGM group, erg, C‘I’ijmii {saihiimmoi R 4: {Bu}. 3, Substitzztmu on ziifmgeu is critically imgoi‘tant. (Ifompiimncis with 31112131 alkyi groups have good activifi}: With iizca'eesing size {3 effects are metals and low potency at or, receptors (Tmnnmmds with very $221325 subsiitumlis have iii-newest activity. Effcds of Smi‘mtimtiou on :flfl};:g»»1101‘e_pinepin‘mt: {LwRiCfipfijfg {V213 {iei‘m’ms} gore (“calf trachea) {Bi-I ROCH—Cfifflfig pl); dam 111): «MM iiafiintrinsic ,‘ activity 363 Rs: H 5.4 {1.0:} 533 {LG} (ifng 59 (to) (if; {if}? (:‘Irrlek‘Hg 5.3 (03) 7’53 (L0) C‘Htcm'}: gin trio) 7.5 {1.0) (:‘i‘KQTEi5}5 7 (u {10) MedChem 563P Conference Sections: Winter Quarter 2009 Tu 1023041220 T473 Th 9:30-10:20 T625 Problem Set # 2 4. Mast 2011mm {ii—OH grcmpg. Fm” maximum effect both a [Eu-OH group and a IiI~OH shouid be presem HO HO H HQ \ :3 HO "‘CHJHR HO CHQFCHfNHR R morepinephrine R 2 H dopamine R : H Rrepiizephrine R : Me epz'niae R : Me The stereoehemisfry of the EOE group is very impartam R-Enantiomem are 11101’€ patent than Senamicmera. Ai arreeeptors this difference is 10-200 fold; however m Berecepmrs differenceg of 304000 fold are noied depending m] the Nesubsfiment ...
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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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problem_set_2_key - MedChem S63P ‘ Conference Sections:...

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