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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 6 page Class Notes was uploaded by Dr. Bridget Stokes on Wednesday October 28, 2015. The Class Notes belongs to MEDC 603 at Virginia Commonwealth University taught by Staff in Fall. Since its upload, it has received 19 views. For similar materials see /class/230692/medc-603-virginia-commonwealth-university in Medicinal Chemistry at Virginia Commonwealth University.

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Date Created: 10/28/15
DEPARTMENT OF MEDICINAL CHEMISTRY Advanced Medicinal Chemistry MEDC 603 Dr Umesh R Desai Steroids l Structure and Numbering cyclopentanoperhydrophenanthrene skeleton Order ring A then B then C then D then 01I 019 then side chain H W Configurational Isomers trans 0139s v w H IIII transtrans trans cis trans trans I Classes and Nomenclature H Cholestanes 27 Cs Choanes 24 Cs Pregnanes 21 Cs CH3 H3 CH3 H H Androstanes 19 Cs Estranes 18 Cs WI u and gorientation Substituents oriented towards the angular methyls groups at 010 and 013 positions are named 3 substituents These are groups that are drawn with bold bonds ubstituents oriented away from the angular methyls groups at 010 and 013 positions are named oc substituents These are groups that are drawn with crosshatched bonds 1 Cholesterol Bios nthesis H 1 H3C SCoA HO H SCoA a acety Coenzyme A S3 hydroxy 3 methylglutarylCoA Hac HMG CoA H c reductase 3 H H 3 H36 H lt lt HO 0 cholesterol R rnevalonic acid 1 Important Steroids Remember structure and practice drawing H3 HO CHa H3 CHa OH OH H H o o 0 Cholesterol Testosterone H 3 HO Estradio H HO cHa OH ICch CH 0 HO Aldosterone 17ozmethytestosterone 1 7ozEthinylestradio Choic Acid Points to Ponder What is the general structure of steroids How are carbons numbered How are rings oriented with respect to each other How are steroids named How many configurational isomers are possible for steroidal skeleton What is 0c and B orientation What is the 3dimensional structure of steroids How is cholesterol biosynthesized What is the key step in the biosynthesis What are the different classes of steroids Which steroid falls under what class 1 Strategy for Controlling Hygerligidemia Current anti Metabolism of Cholesterol conversion to bile acids and steroidal hormones HJC H3 cholesterol pregnenoone I Arteriosclerosis arteries results in atheroscl J Role of Cholesterol increases the risk for coronary heart I LiEoErotein Particles se are noncov proteins lipids incl lipoprotein highdensity lipoproteins HDL I Mechanism of Ligid Transgort Dietary fat with cholesterol C 39 re absorbed in the intestine and released 39 protein lipase acts on ee fa ty acids that deposit in liver After further clean up liver releases VLDL in the blood LPL ks on these particles releasing more 39ee fatty acids and changing them to lDL and LDL There are LDL receptors on the cell membranes of the extrahepatic cells which allow L L entry into cells This is how C reaches cell interior where it is esteri ed and stored Excess cholesterol suppresses the biosynthesis of LDLreceptors so that cholesterol intake decreases Repackaged LDL particles called HDL are t he blood stream These particles are sensed by the liver through the HDL receptors Thus the liver gets constant information as to how much LDL and HDL are present in the blood hyperlipidemic agents target several mech nisms to control DM high cholesterol in serum Ingestion of cholesterol from diet is reduced by cholesterol absorption inhibitors The biosynthesis of cholesterol is reduced by statins Bile acid sequestrants reduce bile absorption thereby enhancing cholesterol metabolism w 39 brates increase lipoprotein catabolism thereby transforming more LDL into HDL Other miscellaneous drugs also exist in market that function through mechanisms which are not clear Bil2 excessive deposition of endogenous products ofblood in facilitate enhanced cholesterol transport in blood alent aggregates of ude triglycerides cholesterol cholesteryl esters and phosphoserines proteins include apo lipoprotein A B C E et articles include chylomicro density lipoproteins VLDL intermediatedensity lipoproteins IDL lowdensity lipoproteins LDL and semmchulemml gt 39 S 1m Imes in2 erzbnrrmn H3 H Liver CheTC acids P7 and gycochoic acid H 7 IaWOChOlc acid P7 m Liver tissues 0 progeslerone disease lipids and c types of ns verylow 4 A m e of lipoprotein particle Eil2Acids WWW ul2512vul m mm 39 5r INTESTINE LIVER quot EXTRJLHEPRTIC h TISSUE um IDL o 39 c 5 mime o 39 o LCAT unanimein lipas2 up mm2m iiiiase F722 fatty acids adlpusE F722 fatty acids adipus2 nissue v tissu2 nunnun Inna Binsan 2539s Cellulov Choleslevol CEIWEYlem to HDYmDHESWlle c2lls uvsluvag2 ul2s nun Lipnpmt2in emahnlism as glen J xx were thought to be rigid and pre crafted to fit into each other perfectly The drug is a key that fits the target the corresponding lock specifically andproductively when thefit is appropriate the desired therapeutic response is achieved when thefit is not MEDC 601 and MEDC 603 Fall 2007 Dr Umesh Desai urdesaivcuedu 8287328 Drug Action and its Measurement De nition ofthe word Drug Drugs are chemicals thatprevent disease or assist in restoring health to diseased individuals Langley and Ehrlich s receptor hypothesis 1 00 years ago Langley rationalized why only certain molecules produced a specific therapeutic response certain cells contain receptor molecules that served as hosts for the drugs the new supermolecule had properties that produced the therapeutic effect Ehrlich coined the term receptive substance or receptor Receptor Most drugs combine with specific sites on macromolecules by precise physiochemical and steric interactions between specific chemical groups of the drug These sites are termed receptors Types of Receptors There are several types of receptors G protein coupled receptors ion gated channels enzyme linked receptors intracellular receptors Receptor definition is changing DNA andRNA are also being recognized as receptors carbohydrate molecules on cell surfaces are also thought of nowadays as receptors enzymes Yes free floating enzymes can also be thought of as receptors however in the common literature one does not typically refer to them as such Theory of Receptor Action Fischer s Lock and Key hypothesis The drug and its receptor V asquot a appropriate the door cannot be opened The theory does not fully explain why some keys open door partially partial agonist or antagonist or why some keys produce an antagonist action or why some keys bring about the formation of the lock J J J Induced t hypothesis gt Complexities regarding receptors mime Sub ENE gt Neither the drug nor the receptor need to be rigid Kw g sunquot sun the zzpper model gl gt Intermediate cases rigid ligand 7 exible receptor A Enzymmwmwex andflexible ligandi rigid receptor the induced fit model gt At least two steps an initial interaction between the drug and the receptor followed by a conformational change in either the drug or the receptor or both that results in tight binding Measuring Drug Action Interaction measured in two fundamental ways 7 affinity of interaction K j and concentration ofthe drug that effects a 50 decrease in the physiological signal Ing The case ofenzyme substrate and the enzyme inhibitor reactions through chromogenic substrate hydrolysis De nitions of agonist antagonist partial agonist partial antagonist activator inhibitor examples of these words K A K 1 K1 1C5 units of these constants profiles of constants with respect to concentration of the drug Quantifying Drug Action and Dose Response Curves Basic principles enunciatedfor enzyme inhibition remain samefor binding to receptors measuring the K1 VVV DEPARTMENT OF MEDICINAL CHEMISTRY Advanced Medicinal Chemistry MEDC 603 Dr Umesh R Desal39 Androgens I Structure of Androgenic Steroids 19 CH3 0quot CH3 0 carbon skeletons presence of oxygen CH3 CH substituents at the 3 and 17positions testosterone is the most important 0 o o androgenic steroid CH3 0H H Testosterone Androstenedione 5a dihydrotestosterone DHD NI Pharmacologic Activities of Androgenic Steroids Two types of effects anabolic and androgenic Anabolic effect refers to development of muscle mass Androgenic activity refers to development of sex organs 0 H C CH 0H NI BiosyntheSIs and Metabolism of quotin Cquot 3 CH3 Testosterone CH CH CH3 HSC CH3 H0 H0 0 Cholesterol Pregnenolone Testosterone CH3 0H CH3 0quot CH 0 CH CH 4 4 Ho o 39 H H Androstanediols E 39 DHD Glucuronides WI Overall Mechanism of Steroid Hormone Action extracellular intran uclear receptor Transcritpion Translation to synthesize prot39 wit intracell 39 0 Com plexation with DNA 1 of i quot quot Relevant quot 39 39 Steroids CH3 0quot CH3 0H CH3 Testosterone H Nandrolone 0 0R CH3 Testosterone esters CH R COCHZCH3 propionate 3 R COCH25CH3 enanthate Oxymetholone R COCHZCH2C5H8 cypionate CH3 0H u CH CH 17a methy testosterone Dromostanolone page I of 2 DEPARTMENT OF MEDICINAL CHEMISTRY Advanced Medicinal Chemistry MEDC 603 Dr Umesh R Desal39 Adrenocorticoids WI Structure and Activity of Adrenocorticoids These are synthesized in the cortex shell of adrenal glands that are located on top of kidneys hence the name adrenocorticoids biochemically they are divided into glucocorticoids hydrocortisol cortisone and mineralocorticoids aldosterone on the basis of their activity Addison s disease Cushing s disease and Conn s syndrome are pathologic conditions related to adrenal cortex and the hormones produced in them importance of adrenocorticoids is most dramatically observed in adrenalectomized animals there is an increase of urea in blood muscle weakness decreased liver glycogen and decreased resistance to insulin lowered resistance to trauma cold chemical shock glucocorticoid activity and electrolyte disturbances mineralocorticoid activity Glucocorticoids regulate biosynthesis and metabolism of carbohydrates proteins and lipids In addition glucocorticoids are affect the immune system and are used as antiinflammatory agents 0 o 0 OH 0 C H 0 0H 0 H Ho OH CH3 CH3 2 o 0 o Hydrocortisone Cortlsone Aldosterone 2 Bios nthesis of Adrenocorticoids 0H 0H H3C R H3C o H3C o o 0 CH CH CH CH CH 3 3 3 3 Ho 3 CH CH3 CH CH CH3 3 gt gt gt Ho Ho 0 o 0 Cholesterol Pregnenoone Progesterone 2 1 Hydroxy progesterone Cortlcosterone R CHZCHZCHZCHCH32 0quot H c 3 CH3 CHO l I OH H 0 CH CH gt o 1 7a Hydroxy progesterone 1 1 Deoxy cortisol Aldosterone l Metabolism of Adrenocorticoids l o R quotOH 0 0 CH3 CH3 OH R quot0H CH CH gt i 0 CH 0 0 0H 0H CH OH H0 0 3 ll 0H CH lt 0 0 o Hydrocortisone Cortlsone 3 OH R 0H Note R H or 0H 1 Biochemical Action Classical steroid hormone mechanism wherein cortisol aldosterone diffuses into the nucleus of cell binds to its specific receptor resulting in the transcription of specific proteins Hydrocortisone leads to lipocortin which is an inhibitor of phospholipase A2 This enzyme is involved in the mediation of inflammatory signal wherein it releases prostaglandins leukotrienes from cell membrane By inhibiting phospholipase A2 lipocortin and hence cortisol behaves as an antiinflammatory agent Aldosterone in turn leads to release aldosteroneinduced protein which regulates NaKATPase pump thereby regulating electrolyte balance page 1 of2


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