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15.8Alkaloids 48t CH" I /-\-cHrcH2_NH2 N\ N-H /cH2cHz-N-CHs *.. l-\ cH,-< \:/ Histamine Pvribenzamine ) ^ \-,"\ .zcH, t<''{"-o-cH2cH'*aar, tl \-/ Diphenylhydramine (benadryl) Benadryl is also a component of Dramamine, a drug commonly used to prevent motion sicknessor nausea. lt, PRACTTCE EXERCTSE t5.tl Identif,i the functional groups in the neosynephrine molecule. what is the physiologic action of this drug? 15,8Alkoloids AIM: Toname ond give examplesof usesof medicinolalkdloids. Focus Alkaloids are physiologically active amines produced by plants. some of the most powerful drugs known are derived from plants. Some have been used for thousands of years.Among the oldest of these drugs are the alkaloids-agroup of ouer 2s00amines obTainedfromptnnts.The name a.lkalgi(, meaning "alkali-like," bears testimony to ttrb weatty uasic properties of thesecompounds. The molecular structures of the arkaloidsvaryfrom simple to complex. Nicotine is one of the simplest. Nicotine Nicotine is one of severalalkaloids present in tobacco. small doses,such as those obtained by smokers, stimulate the involuntary nervous svsrem. Large dosesare toxic and result in nicotine poisoning. Nicotine is a iabituating drug-one on which people acquire a dependence.An addicting drug is one that causesphysiologic changeswhen iiis not used for a time. - severalimportant alkaloids contain the indole ring system.Lysergicacid and reserpine are indole alkaloids.Lysergrcacid is produced uy ergot, a fungus that grows as brown bodies on infected rye. The diethylamid" 6rryrergi" acid is called LSD (lysergic acid diethylamide), a powerful and *ia6fy lb"r-"_dhallucinogenic drug. As little as I g,gof LSD, scarcelyenough to see, is sufficient to causehallucinations. The danger of overdossis highi Reserpine,an indole alkaloid of the Indian snakeroot (Fig. rs.+a), reduces hlpertension (high blood pressure), which, if left unchecked, 482 CHAPTER 15 Aminesand Amides Figure| 5.4 (a) Indiansnakeroot is the source (b) TheCinchona of reserpine. tree yieldsquinine. could lead to a stroke or cardiac arrest. Strychnine, a bitter-tasting compound from the plant Strychnosnux t)ornica,has a long and sometimes sinister history as a poison. CH"CH, "ttl O cH3cH2-N-C N-CHr N I H Lysergicacid diethylamide (LSD) Strychnine HsCO Reserpine The antimalarial drug quinine is an alkaloid that occurs in the Cinchona (pronounced"sinkona")tree (Fig. 15.4b)of the Andes Mountains of South America. Quinine has the aromatic quinoline ring system as part of its molecular structure. Other drugs that act against malaria have been synthesized, but quinine is still used. 15.8 Alkaloids 485 HO-CH CH:CHZ Quinine Quinoline The tropane ring system is found in cocaine and atropine. Cocaine stimulates the central nervous system. It is now a widely abused habituating drug. Atropine is an alkaloid obtained from belladonna, hemlane, and deadly nightshade. It has severalmedicinal purposes, including treatment of certain eye conditions. A tincture of atropine causes dilation of the pupils. Roman women used belladonna to achieve this dilating effect because they thought it attractive. Indeed, belladonna means "beautiful lady." I N N /\ af\ 1/ CH" f"' CH" I N o /\ af\ c-ocH3 1/ V Tropane \ ? o -C-CH /cHzo:u Atropine Cocaine Opium is the raw resin extracted from the seedpods of the opium poppy (Papauersomniferum), not the poppy grown in gardens.When the resin is refined, two important alkaloids, morphine and codeine, can be isolated in pure form. Morphine is the most effective pain-killing drug knovrn. Codeine is a powerftrl analgesicand cough suppressant.It was an ingredient in cough medicines for many years, but it has been replaced by dextromethorphan, a synthetic alkaloid that is equally effective. Morphine and codeine are addictive drugs. Illegally produced "designer" drugs chemically mimic the effects of specific drugs of abuse. Some derivatives of fentanyl are over 1000times more powerful than morphine. Designer drugs have a high risk of addiction and can causebrain damage and even death. CH" CH" CH" N N N I I I o Morphine Dextromethorphan 484 CHAPTER l5 Aminesand Amides Ironically, heroin, an acetic acid ester derivative of morphine, was introduced because it was thought to be a better analgesicand to lack morphine's addictive properties. It was soon found, however,that heroin is no better than morphine as an analgesicand is even more addictive than other opiates-drugs that produce the psychological and physiotogic efficts of opium. Today,heroin is a destructive hard drug. Methadone, a drug that blocks heroin action, has been introduced to wean heroin addicts from their habit. Methadone does not produce the euphoria associated with heroin use. Its use is controversial,since it too is an addictive drug. HsC\ CH. I N N /.CH3 I H3C-CH /-\ ,, o o-c l-,,' /CHS o CH,' / -- \ I \r\ \ / / t \ \ /-91 // o/c", ) fr, CH. Heroin Methadone PRACTICE EXERCISE I5.I2 List some of the physiologiceffectsand usesof (a) morphine, (b) nicotine, (c) atropine, and (d) quinine. 15,9Borbiturotes AIM: To nomeond give exomplesof usesof borbiturote drugs. Focus Barbiturate drugs are derivatives ofurea. Urea has a simple molecular structure. In structural terms, we can consider it the diamide of carbonic acid (HzCOg): o HO-C-OH Carbonic acid o H2N-C-NH2 Urea Urea is important in its own right, since it is the form in which our bodies disposeof excessnitrogen in the urine. Its high water solubility (125g/ 100 mL of water) and low toxicity make it ideal for this purpose. Condensationof malonic acid with urea produces barbituric acid, the parent compound of a number of drugs. 15.9 Barbiturates H H o\ ,/o-H f H-N. /o-H + I oy-t-',o tc:o I H-N I cH2-c\o I \/*-" tl ""utt | +2rl2o o H Barbituric acid Urea Malonic acid 485 Note that barbituric acid contains the pyrimidine ring system. It is an acid because the hydrogens on the ring nitrogens readily dissociate in basic solution to form barbiturate salts. H Na* o\-t--tro o\-*:fo +NaoH- | I \--*-" tl o o Sodium barbiturate Barbituric acid Hypnotic hupnos(Greek): sleep Sedative sedare (Latin): to calm +H2o | | \.,.t-" tl Salts of barbituric acid and its deriuatiuesare calledbarbiturates. The sodium salts are often administered becausetheyionize in solution and are more water soluble than the acid forms. Barbituric acid is not physiologically active, but some of its substituted derivatives are among the most potent hypnotics (sleep-inducers) and sedatives (tranquilizers) knovrn. Barbitalwas introduced in Gqrmanyin 1903under the nameVeronal, and it is still used as a hypnotic. Since the introduction of barbital, medicinal chemists have synthesized thousands of variations on the barbituric acid structure, but only about a dozen are clinically useful. H H oY*Yo oY*Yo I cH3cH,+\-/.N-H Phenobarbital (Luminal) Barbital (Veronal) cH."Yt"lt H H I N\ -o N Y CH3CH2CH2CH-\_,,.N-H cH2:cHCH2 ll o Secobarbital (Seconal) ?fi:*;rr-*-" o o I CH.,Y,.-Y" tll cH3cH2cH2cH--y'\ -NCH3CH'Y o Thiopental H 485 CHAPTER I5 Aminesand Amides As hypnotics, barbiturates are often classifledas long-acting or shortacting. Barbital is long-acting.A 0.3-g dose produces six or more hours of sleepin an adult. Thiopental sodium salt (sodium pentothal), on the other hand, acts only briefly; it is used in surgery to put patients to sleep before a generalanestheticis administered. PRACTICE EXERCISE I5.I5 Write the structure of sodium pentothal. PRACTICE EXERCISE I5.I4 Explain why the hydrogens on the ring nitrogens of barbituric acid and its derivatives are readily lost as protons. s#&#ffiseRY Amines and amides are major nitrogen-containing classesof organic compounds.Amines are organic derivatives of ammonia. They are classified as primary (1";RNHj, secondary(2";RNHR),and tertiary (3'; RNRR).A quaternary ammonium salt has four carbon groups attached to the amine nitrogen; the nitrogen is positively charged.Carbon rings that contain amine nitrogen are called heterocyclic amines. The acid-base properties of amines are similar to those of ammonia. That is, the ability of the unshared electronpair of amine nitrogen to accepta proton in acidic solutions makes amines weak bases.Because of their weak basicity, certain amines act as pH buffers in biological fluids. Amides are derivatives of acids and amines. \Mhen formed from carboxylic acids, they have the general formulas RCONH2 (simple amides), RCONHR(monosubstitutedamides),and RCONRR (disubstituted amides). Amides are neutral compounds; the unshared electron pair of the amide nitrogen is pulled toward carbonyl o)rygen,rendering it less available for protonation than it is in amines. Many amines are physiologically important. The catecholamines are neurotransmitters of the central nervous system. Amphetamine and several hallucinogenic drugs are similar in structure to catecholamines.Alkaloids are a classof over 2500amines isolated from plants. Many have useful medicinal properties. Lysergic acid diethylamide (LSD), reserpine, quinine, atropine, and cocaine are a few alkaloids. Morphine, another alkaloid, is the most effective pain killer kno',,rrn. Barbiturates are derivativesof urea (NH2CONH2).A dozen or so barbiturates are used in medicine, mainly ashlpnotics and sedatives. SEJffi IS&*Y {3FREA€TE*tr5 Here are examples of the reactions covered in this chapter. 1 Preparationof amines.(The amine is 1" or 2'.) HH ll* R-N: tl + R-CI -+ R-N-R 3. Preparationof amides. (a) By dehydration of ammonium salts of acids. (The nitrogen compound is ammonia or a l'or 2'amine.) o? CI_ R-c-o NHr* # HH Tieatment with base liberates the free amine. 2. Preparation of quaternary ammonium salts. (The amine is 3'.) R-N: II RR + R-Ct -----' *-'{a* Cl + uro (b) By reactionsof ammoniaor amineswith esters (Theamineis 1'or 2'.) or anhydrides. oo r R-C-OR RR n-t-NH, .. + H-NHR oooo llli..,,..l R-C-O-C-R -+ + H-NHR l R-C-NHR + ROH --- R-C-NHR + R-C-OH
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