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by: Dr. Bridget Stokes


Dr. Bridget Stokes
Virginia Commonwealth University
GPA 3.91


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Class Notes
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This 43 page Class Notes was uploaded by Dr. Bridget Stokes on Wednesday October 28, 2015. The Class Notes belongs to MEDC 310 at Virginia Commonwealth University taught by Staff in Fall. Since its upload, it has received 41 views. For similar materials see /class/230694/medc-310-virginia-commonwealth-university in Medicinal Chemistry at Virginia Commonwealth University.

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Date Created: 10/28/15
Sickle Cell Anemia Disease LECTURE OUTLINE Origin and Physiology of SCA Genetics Molecular Basis of SCA Clinical Features ofSCA Treatment of SCA Case StudyrSH MIF mm mm sac I mm OxylbA and DeoxyHbA 1 mamm mombe have mum mm canfammhms 2 The MD exmsm equl mum nmm mm Sickle Cell on egt v1 muh nn p5 uun39ng nnnxw39nn uI mum men mambo1 in denth s imulnhl IngL Hmmzygntn anuylnptnmni Hunmzygntzxdzvghp scn Thzy mxmmi nny dwehp painful gimme uIvuuruuhuile u39in39 multinginnmxhidilyuld damage in mm emy impurlam gm Pndumilun y mum people uIA inn detail mun in us and gt 3 ml39ll39mnwux wile mm 1m 1m m m 151quot mm muer m u an mm Sickle Cell Anemia Distribution 1 on nmm L m M Odds of Getting SCA in the USA About 1 in 12 black families in me USA are carriers ofme disease heterozygous About 1 in 144 black families have bom mother and faiher as carriers ofmese 144 families there is one chance in four of having a sickle cell baby homozygote 11m makes approximately 50000 homozygotes in me USA A 39 A 39d d P t 39 Polar Side Cha us a Uncharged Nonrpolar S de Cha39ns too c0039 00 39 coo coo coo f 39 H NtciH H N tJ H H N f H N trquot H w I H H N t H H quotLC H H f OH H C OH H2 H2 H H f H l Aquot CH 2 H H H H CH H CH CH2 Serine Ser or S Threonlm Thr or T Cysle m Cys or C Glyc m Gly or G Alan m Ala or A I Valine Val or V 5 Eco COO 50039 H iH H N H H N H H quot C H Tyros m Tyr or Y Memion m NIel or M IHZ EH2 H2 coo so 2 i n i H2quot H N o Him H quot f H H2N c H H w c H H N t H Asparag39me Asn orN 2 H CH2 CH H CH CH2 H26 2 I Glutamlne Gin or Q Twmhophm TIT or W lH CH2 H2 2 Prolne Pro WP 3931 H c CH l 39 l b Add 0 Basic Lem Lm or L Iso euclne I e or I Phenylalanlne Phe or F 3920 I coo 2 H N t H H N tl H H N tJ H H Mtg H H N H tH2 EH2 3sz 2 CH2 H cH H2 2 2 H o Rquot JIHZ H2 Ht 1 Asparlate Asp or D H Hquot HCH2 2 Glutamate GI or E HH MHZ lis dine His or H Lysne Lys or L NH2 Arginine Arg or K DNA and RNA NI 0 0 OH it m H2N o N o H2N N o H H N OH Nucleotide base sugar phosphate Nx thymine cytosine RNA Chain ofnucleotides adenosme monophosphate DNA Chain of nucleotides forming a HN O FNH double helix N N N NVN o H 0 guanine adenine uracil H2 739quot N N I ltN iNJ a A H H0 0 NH2 39 h gt quot N N L i 0370 ltN J O The Making of Protein from Information Stored in the Genes t id mainHm rimn Int Pammm swarm lat PWMMEUM oi mining DNA consists of four DNA different nucleotides Adenine A Guanine G it 39 Thymine T Cytosine C Tramch ion 3 Transcription 7 r r Conversion of RNA iranScrIm sewes iraciw 15 mRNA mformahon from in HDH Jli39f i i pr EbSEd ID became DNA 0 mRNA m NA in eukaryntra l 3mm Translation Conversion of m information from RNA to protein F39nlypepiiizi GUG CAC CUG ACU CCU GAG GAG AAG val his leu thr pro glu glu lys Muh nnul CTC GAG in RNA m CAC cm in RNAin the an mm nmhsinlllz rephcemenl ufGIu wilh V2 cm 395 z mgzlively chzxgzd 2minu uidwhib Vzlllzs m chaxgz Inheritance arm sickle cell gem AS um m pznm ikk een Inil ur llztzmzygnus AS m eunwu gems umhulhpmnts sy dcklz een ding ur Immuzyguus Dmxy Hh Polymerization of HbS x V the heme A M he mt 1 0w deuxyHbS suck tugether and EventuaHy petymertze m the REC 5 ts very setubte mgat mte deuxyHbS has reduced setubmty HgdL Factors affecting HbS polymeriution 1 Oxygen Ensmn 2 pH htgh pH mmbtts stckhng 3 HbS cuncentratmn 4 Temperature mereases REC stckhng 5 Presence ufutherfurms eer HbF HbA Proposed Mechanism of Gelation Hofrichter et a1 1974 Treatment of SCA the disease Femnllm pmphylaxls Fulate gunmanan Pharmaculugxcal mudh auun ur fetal hemnglubmHbF 7th hydra a dentabmeand butymte Oplmd analgesic hat pamm epxsudes Other pnten al treatment m39 cur Gane replacanem 7 unly mauve mmpy HbS m dl a39s rAnusxcklmyAnugellmgagems Iwn types 17 mm m DenxthS7 Hb Modi ers r Mechanism of Action anmmmmmmmm mumquot mm mmulanmv nan Wham mu m nummawnns u 1me mum 939 i g 3me AntisicklingAntigelling Agents Most quhese agents were developed in Lhe7 39s and an s GIG h n mm o mammonw m m News Qquot N 0 new Therapeutic Ef cacy Heterozygotes moono Hb A are asymptomatic 2030 Hb F Saudi homozygotes have mild disease 20 5ono Hb s modi cation may thereiore be needed ior Lherapeu c eilieaey 4 L blood oi 25no hematocrit corresponds to 322 5 g 5 mM oi Hb s Translates to about 17 2 g of compound mol wt 100 r 400 for 20750 quotn Hb S modification 5HydroxymethylZfurfural 5HMF HUM o CHO SHMF pasteuriled milk etc SHMF is armed rum hrmkl lnwn or sugr in wrinlls sugreonminingiood ammu acid and areducmg sugar SHMF is also fnrmad rum hrnwning nf mgr caramellzanun SHMF is readily water snlllhleznrl mhlein solution at room temperature Reported Lil5n in rats is 25 r 5 gkg rune u 1 m m o m s1nm loommu u e I Humor ssz nns mummy m 55 we Dame and ma mums Wm am can emralmnsmSHMFunderhwuxmcondmunA39huxwenSslhmir gm all mrahr Sickhngmcdiismmmiedmadosedwmdem manna SHMF Increases Hb Oxygen Af nity 55 Cells quot2quotquotme mam m three dmaem mncmm onsm 2 5 mm SHMF oniheshave and Pusmon mm as m smug m M1 Qromihae Cd s Yhe mm mm airman mad Sed vendem mm mmconmmmmsweasmm s moreand Newman SHMF In Viva Studies UsinE TE Sickle Mice A w a u quotmm mm Approaches to Drug Design LEMDNYB we we ViaVEmths Med em SeniaiFeluu mam Objectives of Drug Design Create a biologically active agent Create a clinically useful agent a curative powers a pharmaceutical properties a ADME a Few Sid a Econorn Patentable e effects ical BIOLOGICAL ACTIVITY 7 MAY BE INFLUENCED BY CHEMICAL CHANGE r MODELED AS A MATHEMATICAL RELATIONSHIP TO STRUCTURE r PREDICTION OF STRUCTURE CHANGE IS AN OUTCOME OF A GOOD MODEL rm r44lt LJ L r lt96 V f i f1 ml hmlmJ mm Y wx Law 237 eikk g DEFINITIONS 0 Pharmacophore A constellation of atoms in a molecule that are essential for a particular biological effect It is believed that the pharmacophore is complimentaryto and interacts with a receptor r enzyme ac ive site Receptor A region ofa macromolecule usually a protein whic engages an active drug to produce an effect RECEPTORS 0 A molecular fragment ofa cell component hypothesized to interact With a drug neurohumoral transmission enzymes allosteric sites DNA sites Receptor Characteristics generally speci c o en stereo selective may be interfered with quotisolationquot fraught with dif culty menapu Pmuynszc um quotW www Magnum v on u mqu Iw xmx Mmquot mum Lead Discovery Screening Chance Discovery serendipidy Natural Products Exploit Side Effects Metabolites Endogenous Substances Combinatorial Chemistry QUANTITATIVE STRUCTURE ACTIVITYO RELATIONSHIP QSAR The quantitative modeling of biological activity resulting from property or structure changes in a set of molecules QSAR MODEL 0 Activity aVariable 1 bVariable 2 Use a successful model to predict and design new candidate molecules Variables must be interpretable as structure information to the synthetic chemist No physical property is directly interpretable as structure What variables do we use OBJECTIVES AND GOALS OF QSAR Quantify the relationship between measured physical properties andor biological events and the molecular structure or its surrogate PARAMETERS DESCRIBING THE MOLECULEQ ARE FROM ONE OF TWO SOURCES Physical Preperty Structure index index Hammel sigma Molecular orbital indices pKa ceemetrre Es1imal2s TallSlevi Molecular connectivity Elemvulupulugical s1ales Lug P Kappa shape indices zun igt 53 w m m 539 2 gm W h n H any my WWW Maw umvhHQW Wm mmquot quotumHMMMW Mulcculnr Cunnm vin mum smumxmn 32 32lt a a 5mm um mm s nmlkaubsmutaw l U m m m m W A h Mn mlmlmmu men mm mmm m y 39 1 1m m m n MW 1 mm my Wluu M x mm m quotmquot Wm M smmw Haw1 2H1 2M 3 n 2 zra al kxu mm 24 sum n rw 1 my mm m a w my w x mmcu mwrnnm muvcf c 5 73 3 nail 2 2 222 a E E in is 5 ii 52 5 y 55 3 221 mi 5E5 mum m mm mm mmmmmamlsumysm s s mimu mum m m TB39E ELECTROTUPOLOGICAL STATE The ESlare fan 2mm group S 15 swaL The Esra value enemies we elemamc d Ingaln mm 2 an anal xiixacwx nagdung n2 valence mw smecuxe andns relaunnshm a all ache axons in the mnlecule STRATEGIES 1 Use OSAR m mea e mudg s ve atmg s1mcuve m pmpemes and amwny 2 Usemude smdeducempunamstmcmve eatuves mme ead cumpuund 3 Use mudg stu dwe up a eusnmsme pmme uhmpunam shuntuv eamves a descnmuv quotand ana ysws A Usems Wannath m seavch data bases m m syntheswze ana ugues Use of Databases Select data bases of congeners of lead compound Select data bases of compounds with related activity Select large heterogeneous data bases Activity or Property I Molecular Structure Representation encoded in QSAR QSPR Models Molecular Connectivity Indices Kappa Shape Indices Electrotopological Indices Molecular Struaure HSA Binding for iLactams p PAB 119 STArom gt sum ofESlate for aromatic carbons 144 R2 11quot gt chi valencertwo for R2 substituents 534 R1 dquot gt zero order di erence chi index for RI 126 ST7F 1 gt sum of ErSlale for 7F and 7C 381 R2 STrCHr gt sum Estate for 1117 R2 substituents 560 STN7 gt sum of Estate for N7 atoms 7 0 520 C ST0 gt sum of Estate for 0 outside scaffold r 211 R2 HSTAmine gt sum of hydrogen Estate for rN39H 71 and rN39lr or R2 substituents Leave 10 out whole set1 ten times E 109 q2 078 Structure Interpretation D Protein Binding Increased by gt increased electron accessibility and sI Arum and R sI 7011 number of aromaticsaturated carbuns gt increased branching in RI and R R If and RI dquot gt increased electron accessibility and 51 Nr number of unsamrated nitrogen amms gt increased electron accessibility and sI 7F 7C1 number of halugens Protein Binding Decreased b gt increased electron accessibility and SI 0 l r number of carbuny g oups outside core gt increased hydrogen accessibility and R HsI Amine number of amine groups in Quantitative Calculations Done with Equation Model BloodBrain Barrier Penetratiori 0 Model logBB 000661 HSTarom1gt Sum H EState for aromatic CHs r 0104 dzxv 1 gt Difference chi valencetwo index 0145 HSTHBd gt H EState Sum for H Bond donor 0369 Qv gt Polaritynonpolarity index 00143 ST7F 1 gt Slim EState for F and Cl 7 0392 thernal l est bet 3 drugs Liu et al JCICS 41 1623 2001 MAE 012 rms o 15 r2 094 Structure Interpretation p logBB increased by gt increased electron accessibility and HSTArom u CHs m er of aromatic gt decreasing skeletal branching dzxquot gt increasing nonpolar character Qv gt increasing electron accessibility sTF C n C logBB decreased by gt increasing numberstrength HSTHBd of H Bond donors Quantitative Calculations Done with Equation Model I Descriptor Percent Contribution Range Qv 40 101 nonizero cpds 0 to 100 dzxv2 22 97 nonizero cpds 005 to 63 HSTHBd 29 62 nonizero cpds 111 to 56 HSquot39arom2 23 67 nonizero cpds 07 to 55 ST7F7C1 30 22 nonizero cpds 35 to 84 Fish Toxicity Full Data Set Model PLcso 0559 1x gt Chione valence index 0280 me gtMaximum Hydrogen EState in cpd 00610 STCl gt Atom type EState for chlorine 00726 STO gt Atom type EState for ether oxygen 158 r2 087 s 025 F 140 n 92 External Validation pm 026 LOO Test Sets structureInterpretation of Model Full Data Set pLC50 increased by gtdecreased skeletal branching 1f and increased general size gtincreased polarity and number of Hmax polar hydrogen atoms gtincreased electron accessibility and sTC number of chlorine atoms pLC50 decreased by gtincreased electron accessibility and ST 0 number of ether oxygen atoms PB 225 STArom 146 R2 11v 135 STrF 1 gt sum or Estate ror aromatic carbons gt an valencetwo ror R2 substitucnts gt sum or Estate ror 7F and 7C 444 R2 ST7CHT gt sum ofEState or 431117 ror R2 substitucnts 7211 R2 HSTAmine gt sum or hydrogen Estate for erl2 132 5quot NH 7 ton R2 sub stjtuents Prediction of 13 391 commercial penicillin s r2 080 s 121 F 60 n 74 q2 076 amx 134 MAE 127 r2 084 HS Binding for Penicillins Model Bird and Marshall data Structure Interpretation D Protein Binding Increased by gt increased electron accessibility and sI Arum and R sI VCHf er or aromaticsaturated carbons gt increased branching in R R If gt increased electron accessibility and 51911431 numb er or halogens Protein Binding Decreased by gt increased hydrogen accessibility and R sH Amine number or amine groups in Quantitative Calculations Done with Equation Model Based on information in extended chi indices we developed models for liquid density For 82 alkanes 5 07348 029291x 00030 3x r2 09779 s 00046 n 82 Models for other classes of compounds were also developed L B Kier and L H Hall Molecular Connectivity in Ch enuzrtry and Drug Research pp 4214 Academic Press 1976 Future uses of Chi Indices as part of QSAR models 0 Example HIV Protease Inhibitor Binding pIC50 0374311quot 7 0703 11 0176 SHTother 0693 HsCu 0517 SHTHBd e 2 915 r2 085 s 062 n 32 rzpm 073 111m solute M Katherine Holloway et 21 A PrioriPredicu on of Activity H 0 0 for HIVJ Protease Inhibitors Employin gtrt rn Energy Minimization in the Active Sitequot 0 o J Med Chem 38 305317 1995 r1 078 rim 075 EState Analysis Salicylamides pCso 438 e034 57 255 e050 58 2926 e283 2 089 s024 F88n25 rzmss 086 s 027 To improve binding use substituents at position 3 with smaller I values at position 5 with larger I values AnIlLeUKemlc ACIIVIty 0T r O A R1 J Cough and L H Hall J Chem Inl Comput Sci R IV 39 3567361 1999 pMED 0208 IXV Skeletal branching 2112 xvpc Branching adjacency 0338 ST39CH3 EState for methyl groups 0128 STar0m EState aromatic carbons 5071 r2 090 s 021 F 70 n 37 r1 085 s 026 press press Tropane Dopamine Transporter Binding 6 10x Em 0 J Gnllg1 and L H Hall nmpm Sci 40 127071275 2000 r 0589 SKIother H E late Nonrpolar r 0327 11quot tate HBond donor is IEBd H Jays 7 0568 Hsc4 H Esme atom 4 r 0117 sum1 Ers ate methyl groups 7 16342 12 084 s 032 F 27n 25 a 5quot 0 Wquot 039 2 r 1quot 03977 51quot 12 075 MAE 028 MOLECULAR MODIFICATION Have no background knowledge Make many compounds Test each until one is successful Tne MudeIing Paradigm in Drug Design IminI lt7 ininmiuon Physicochemical Properties in Relation to Biological Activity Van Zhan PhD Department of Medicinal Chemistry yzhangzvcuedu I A Drug Distribution and Pharmacological Response Drugin nmmlaw39nn llgllhln rlginhhud myquot wanmm 1 Absorption pH values m each pen uluuv Gllvacl lumach 173 Smalllnleslme 7 large lnles1me 778 2 Protein Binding 3 Membrane Structure Plasma Membrane Structural Components 5 rm mieln carom1m V Pl Hum mu sue aIn yRegfon u um um Yucatan H dm hchlc Viagraquot mm MMogalo HyR m mu em ne Model 9 on mnsmemmne Protein I V lji Phospholipid Molecule quotWWW rm Mumwm uIi l The unique chemical structure of decides the character of the membrane architecture 39 Passive Diffusion I mmpurlm Llnlprm nwlnulm I l l llm i li Wm M mum Mkmi iu in hulkmi uni iiiiiiiiiqiy i mmw quotmum slur di uslnn Fadlimed dlltusinn Active Transport tnwvjmximm a 4 J V A wm d v mm s o Miawe f ii i Em 4 km r u v a a 39 1 4 Distribution and Excretion W l Afterthe absorption 5mm 9 drug Ci quot39 39quot quoty V molecules will act on l conjugation H target site some may magnum smnieAaaucts eme a olize j in Eventually all the I WV 53quot drug molecules zoningalion a would be excreted from our body Renal Ellmlnatmn mm ADME warm mlwmmm I Absorption I Qistribution I Metabolism I Excretion I onicity B Properties that In uence Passage of Drugs Across Membranes 1Partition Coefficients water Drugnuznnl p Drugwaer The higherthe P value is the better u s normally do not cross membrane a easy 44 2 AcidBase Partition l HendersonHassalbach equation pH pKa log The nil value at the snlulinn in whi drug 39e a sowed base om acid form A constant in any given mnleeule Exam ple in the stomach 2 54 5iogBA 720 m00BA How about m the smaii intestine 7 54 5iogBA coo 3iogBA 10001BA 39b pr f quot Conciuaion inthe stomach ib mme acid form which iSi pKa 45 itS base form cHarged mode easierto b smaii intestine it i5 the oppo uprofen WiH mainiy be e55 poiarcompar With a sorbed Onthe otherhan d inthe Exam pie 2 in the Stem ach m r7iogBA quotH2 110 00 000BA Amphmmine inthesmaiimtestme 7 pKa92 Conciusion in the S mach amphetamine Wiii e which makes it SUH not easiiy absorbe C Properties and Biological Activity 1 orces Example Receplnr types 2 lsosterism and Bioisoterism Comparison ofPhysical Properties of N20 and cc2 39 lsosterism replacement or modification of functional groups with other groups having similar perperties Grimm s Hydride Displacement Law 39 Burger Bioisosteres are compounds or groups that posses near equal molecular shapes and volumes approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity Bioisosteric compounds affect the same biochemically associated system as agonist or antagonists and thereby produce biological properties that are related to each other Classical Bioisosteres groups within the row can replace each other SH Cl Br llJ H F OH NH orcHJ forH Monovalent Divalent Ring equivalents FH ecseco DHN ecerecce OOQQ Uracil While uracil is Examples for Bioisosteres 5Furacil an anticancer agent substitution of one proton with u o another anti agent 5 F urac 3 Geometric lsomeric Aspects of Biological ActIVIty onne atom lead neoplastic il R N I HZNDZS 390 RCl Br era lorthe thiazide diuretics different ns do not change the are significantly different Another example 195 Ho H0 H OH trans cis Estradiol Diethylstilbestrol inter atomic distances between the 0H grou s In rans bestrol and in estradiol are similar accounting for the greater estrogenic activity of the trans isomer 4 Conformational Aspects anti or SIEQQEred of Biological Activity While anti or staggered conf 39 NMe or atlon ls more H stable lowest energy H H eclipsed onei not COCHJ lo 39 al favorable for acti ity of acetylcho ne eclipsed 5 Optical lsomerism and Biological Activity Stereochemistry amp Chirality stereochemistry deals with the rrangement of atoms and groups in three dimensions stereoisomers are possible when there is a chirality in the molecule Chirality is due to asymmetry Chiral center chiral axis and chiral plane Optically active Enantlomers chiral islhc ccssa and 7 sugncicm cnndi imam c cxslcncc n1 cnammmcis Enam mcis arc mm superlmpnszhle mirmr images nl nnE annlhcr liars cnmmnn slmclural characlcrisl is as well as most nl hcsamc prnpe phys cal and chcmical shnwomical acr y Tndzywe rca zc lhal mnsl naturally occurring medicinal as oummc Ephedrine and Pseudnephedrine Almnsl hall numhcr nnhc drugs in usc arc c In lhc casc nisnmc drugs lhc mhcr cnaminmcr can cvcn hc harmlul l 5 Ma up a Lelulanded a a mum handed in m lhurm en mam Aspanamc nm 53323315quot WW9 quota39quot Ihurmfen 5quot quot SW 1 may than killer In MW slightly hmcr squot m I Importance of Chirality I Pharmacological Am ilyln receglnr The n9 spec39 y nla chiral icccmnrsiiclnr achiral mnlcculc is usual ime launurahl imcway mcric Pnleng In cnan drugs potency dl erencvs may ar39sc hccausclhc mmc 39 mcr cnnlnrmalinn Shijun Zhang PhD Of ce McGuire Annex 125 MCV Campus Tel 8046288266of ce 8046288265 laboratory Email szhan92vcu edu wowmnaxa DID I Bum THAT THING Bone Loss In Dngs Alzheimer39s Disease AD AD A progrsive and faral brain disorder Dr Arms Arzhormor Frau Augusro D 18644315 185mm pamological Hallmarks Senile plaques and Neurofibrillary Tangles T mes tag V What Do We Know About AD 1 The most common form ofdemenua 70 1 What 5 DEMENTIA genera term for 05 of memory and omer merma abmues severe enough to mterfere Wm daHy We What Do We Know About AD 2 OthertvDEs cf demenma 1 a wa2d demenma What Do We Know About AD7 2 Prugresswe and fata brain disease wig 1m8gt55hasnD13 a Every 71 secands sameane deve avs no m man evew 33 secands Projection of AD Devei op merit By 2050 25 of people living in developed countries will be over 55 z u 14 u m 1R0 n are expected to develop AD Our Bram Bram stem The Neuron Forest Comparison of Normal and Alzheimer39s Brain Hea w brew A zhexmer s bram ove ap Svmptoms OFAD 1o Warmng stgns ofAD Mem my 05 D f m ty perfurmmg fammar tasks prcmem wtth anguag a dment th abstract thmkmg Mtsptacmd thmgs c ng s 89 33388 Changes m persnnahty 1n Lass cm Mauve Rtsk Factors gt Age 255 years ctd gt Fam y mstcry gt cenetcs Apuhpmtem E724 Apogee gt Head mdry gt Heart heath How Can We Deve op Agent To TreatAD7 We don 39t have cure for AD currently 1quot Medtctrraw chermsts Haw can we dc m i understand the under wnu mechamsms and Smna cascades mvnwed m the deve nument nf AD 1 chnhnermchvpnthests 2 Amed hvpnthests 3 Tau hvpnthests Cholinergic Hypothesis Symptomatic treatments Choiinesterase inhib tors Symptomat re ef NMDA receptor antagonist Cholinesterase Inhibitors H300 H300 Orb Acetvichoiine Donepezii Aricept Ber 10 mgd Tacrine Cognex 40 mgd Gaiantamine Razadvne 16724 mgd Rivastigmine Exeion 376 mgbid NMDA Receptor Antagonist 0H3 H30 MementineWamenda 1o mgbid New Directions in Treatment and Prevention Semie Piaques and Neurofibriiiarv Tangies r nanny cells Amvioid Cascade vaothesis APP 5APPB SAan 39Sweim nrsecvelase AB fibriiniignmers mnwim quotmam mnnm 0mm H2255 mo 2m 22 mm potennax Targets Based on Amv oxd vaothesws 1 BisecretaseBACE1M2mapsm 2 2 vrsecmase SAB vemuva 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