Xyr

Certain amino acids Nucleic Acid Bases Figure 7-8. Outline of folate scheme. (For the chemical details of this scheme, see Figures 4-13 and 2-3 and accompanying discussion.) duce two clinical advantages. The first is synergism, which is a combined effect greater than the additive effects of the individual components of the drug product. In fact, a combination of TM and sulfadiazine at one-eight of their respective ED50s had an antimalarial effect equivalent to the ED50 of either drug singly....

Sq 81402

The evolution of Aztreonam. having a demonstrated low affinity (high Km) for these enzymes. With respect to P. aeruginosa it was shown that aztreonam inhibited 250 strains of this organism resistant to piperacillin, cefoperazone, and most aminoglycosides, at MICs of less than 6 (ig ml. It is interesting that 3-acyl side chains analogous to those of the cephalosporins show closely similar antibacterial activity against Gm- organisms. It is curious that the analogy even extends to...

O

Triazolo-type 1,4-benzodiazepines lacking the 5-phenyl group began to be researched in the mid-1980s. Some exhibited enhanced anticonvulsant and anticonflict activity in animals, while having a weaker muscle relaxant action and atoxic properties. Monkeys treated for two weeks with several such compounds did not show withdrawal symptoms on challenge with a then-experimental BZD antagonist RO-151788. This drug had been shown to be effective in reversing the effects of BZDs that were used as...

Opiumand the Strong Analgetics Emanating from It

Opium is the dried exudate of the unripe capsule of Papaver somniferumVarieties of this plant have been cultivated and used for several millennia. Today, it is grown in Turkey, Iran, Afghanistan, Russia, China, Southeast Asia, and Mexico, as well as in other areas of the world, both licitly and illicitly. Crude opium is known to contain over 25 different alkaloids that can be chemically divided into two categories the phenanthrenes and the ben-zylisoquinolines (Fig. 5-7). Only morphine,...

Plasminogen Activators

Plasminogen activators (PAs) are serine proteases with high plasminogen specificity. Hydrolysis of the proenzyme yields an active two-chain serine protease plasmin. Plasminogen can also be physiologically activated by the intrinsic system (see earlier), specifically by prekallikrein, factor XII, and a high-molecular-weight kininogen found in the plasma. More relevant to clinical applications, however, are the enzymes of the extrinsic system the serine proteases to be considered. These enzymes,...

Cooh

Benzoic Acid Stlicylanilid (Salundec) Re *cmoI CH2 CH-(CH2), COOH Undecylenic Acid (and aalu) CH3-(CHi) -COOH Capiylk Acid (and aalu) CHj-CHj-COOH ftopionic Acid (and wits) Figure 7-10. Synthetic antifungal drugs. A number of fatty acids possess antifungal properties limited to dermatophytes (Fig. 7-10). Their mechanism of action is not understood. Acetic acid, as glyceryl triacetate (Triacetin), is used in cream form against tinea pedis. It apparently acts as a pro-drug, slowly releasing the...

Mopa

Metabolism of dopamine (*Step not definitely established COMT catechol-O-methyl transferase acronyms derived from underlined letters, except H O, i.e., hydroxy oxy). inhibitors. For example, deprenyl and pargyline, both of which are benzylacetelynic compounds, are irreversible inhibitors of MAO-B5 clorgyline of MAO-A. In summary, unlike with cholinergic neurons, where termination of action is rapidly accomplished by a single efficient process, hydrolysis of the neurotransmitter by...

Carbacol And Pseudo Che Enzyme

B The values were obtained at different times by different methods. The partial double-bond character of the ester may not always have been taken into account. Some were theoretically calculated (Kier). b The values were obtained at different times by different methods. The partial double-bond character of the ester may not always have been taken into account. Some were theoretically calculated (Kier). much as the removal of two methyl groups. The primary amine aminoethyl acetate is inactive....

Cch2ch2ch2n

3 Persistent, meaningless movements characteristic of catatonic stupor. DA agonists (particularly D-2) are also of therapeutic and theoretical interest. They could add therapeutically to the few available drugs to treat Parkinson's disease, acromegaly, and hyperprolactinemia (e.g., bromocriptine, pergolide, Chapter 9, Fig. 9-2). Such compounds theoretically may aid in the characterizations of DA-receptor geometry and topography that have not yet been satisfactorily established. A large number...

Info

LxlO10 1x10 1x10-* lxlO7 lxlO6 1x10* 1x10* ,Minormophine (Omedudone pentazocine emoiphinc phouzocine 6 dihydrtrnwrphinc oxy morphea* lxlO10 1x10 1x10-* lxlO7 lxlO6 1x10* 1x10* so (m) inhibition of electrically induced contraction of guinea pig intestine b y agonist or k, (m) inhibition of opiate agonist activity by antagonists Figure 5-15, Correlation of receptor binding and opiate activity (Creese and Snyder, 1975). Studies on the regional distribution of the opioid receptors in the brain of...

J

Blood clotting. (This represents an abbreviated scheme. Roman numerals indicate clotting factors as listed in Table 11-1). the blood-clotting process, it involves the thrombin-catalyzed removal of two small peptides from fibrinogen, a soluble, circulating, very large (350,000 daltons) special protein. This results in a still soluble fibrin monomer that is subsequently polymerized to an insoluble fibrous substance called fibrin. The irregular mesh formed entraps red cells,...

Neu

Design of renin antagonist (see text for explanation). group of Leu in the natural substrate with a 20-fold increase in inhibitory potency. The SO2 group, E, represents a bioisosteric replacement of the peptide bond of the Val-Ile region. The most remarkable aspects of this study were probably the successful replacement of the bulk of the angiotensinogen polypeptide with a small hydrophobic wo-propyl group, F. This compound, which was tested in salt-depleted cynomolgus monkeys,...

Indirect Sympathomimetics

Indirect sympathomimetics are drugs capable of actively entering the adrenergic neuron and its vesicles to displace NE from its binding sites. Thus the sympathetic effects observed with such compounds are actually elicited as a result of receptor recognition of NE, and not because of any affinity for these drugs. This is particularly true the more unrelated the compounds are to catecholamines or phenylethylamines in structure. Such agents may retain partial direct activity because they have...

Adrenergic Concepts and Synthesis

The biochemical properties of the sympathetic (adrenergic) system are better understood than some of the ramifications of its physiological functions. As already mentioned, postganglionic sympathetic nerve endings elaborate norepinephrine (NE), which is eliminated from storage vesicles within the nerve terminal. Another important biogenic catecholamine1 is epinephrine (EP, adrenalin), which is produced by N-methylation of NE in the adrenal medulla, a gland on top of the kidneys. Unlike NE, EP...

001

The chemistry of the 4-quinolones. Nalidixic acid (ND) (NeGram) (Fig. 7-1), the prototype of this family of drugs, was synthesized as the result of the discovery that an impurity, isolated during the preparation of the antimalarial chloroquine,2 had significant antibacterial activity. It was introduced into therapy in 1964. The antibacterial spectrum, however, was relatively narrow and did not include Pseudomonas, anaerobes, and Gm+ bacteria. Nevertheless, the drug, and two...

Otp

Possible nitrate mechanism of action. pressure after load. Such decreases in preload or afterload reduce wall stress and 02 utilization by the heart muscle. The fact that NTG dilates both large and small arteries, which results in lowered systemic vascular resistance and blood pressure, is also to be considered. Both factors, then reduced preload and afterload reduce total 02 demand by the heart muscle and more than offset the reflex tachycardia induced by the nitrate-caused...

Neurochemistry of Mental Disease

Can abnormalities in the steady state of biogenic amines (NE, DA, 5-HT) and other neurotransmitters of the CNS be causative factors in mental diseases such as schizophrenia, endogenous depression, and manic behavior Only 50 years ago arguments in favor of such a notion would have elicited, at best, benign smiles of amusement from an audience of psychiatrists. It is interesting that some experiments in the 1880s had suggested a possibility of chemical factors affecting the pathology of...

Beckett And Casy Model

Beckett And Casy Model

T-butyl Buprenorphine CH3 Diprcnorphine * Actually hydrog nation is carried out before the Grignard reaction. ** Cyanogen bromide N-demethylatcs the compounds. *** NaOH selectively cleaves the phenolic ether. Figure 5-12. The oripavine compounds. not to affect the tertiary OH) resulted in corresponding phenolic compounds with extremely high potency. The most astounding compound, etorphine (Fig. 5-12), revealed potencies up to 10,000 times that of morphine in animal models. It is interesting...

Oh

HO ( jVc-CHj NHj 3,4-Dihydroxymandelic Acid (DMA) A simplified chart illustrates the peripheral neural systems. It indicates the voluntary motor neurons to the skeletal muscles of the body and the autonomic system that utilizes chemical transmission at five synapses the two ganglia and the three sites where innervation to muscle or organ occur (Fig. 8-4). It will be noted that ACh is the transmitter at four of these sites, while only one utilizes NE. It must also be appreciated that while ACh...

Xqn

The lipoidal characteristic of the GC steroids needed to facilitate epidermal entry can be achieved by various derivatizations of OH functions at C-16, C-17, and C-21, specifically esters and ketals (structures B and C). Derivatization of even one hydroxyl can be useful. Table 14-4 gives examples of the type and positions of derivatives that impart increased lipoidal characteristics to steroids to enhance their local antiinflammatory activity. Dioxalones, which are formed from diols that are...

Chapter

Basic Considerations of Drug Activity Voltaire (1694-1778) stated, Therapeutics is the pouring of a drug of which one knows nothing into a patient of whom one knows less. The medical and pharmaceutical sciences have been working diligently to ameliorate both aspects of the problem. The progress made, especially in the period following World War II, has been impressive, if not astounding. However, there are many important riddles still to be solved and much to be learned. One of the areas of...

Vt

Antiviral drugs. (Trade names in parentheses.) virus, influenza virus A and A2, and parainfluenza pseudorabies virus. The only officially approved antiviral clinical use of amantadine in the United States is for prophylaxis of influenza A2. Amantadine is not active against influenza B. Efficacy has been established. Effectiveness of the drug in preventing Hong Kong flu was reported in 1970. A more recent report also demonstrated the prophylactic effectiveness of amantadine against...

Iii

CR -(CH2-CH2K. C5H5X, or -CH2-OC6HsX. Figure 7-11. Synthetic evolution of antifungal imidazoles.' Extensive SAR studies showed that the imidazole ring is crucial for broad-spectrum, high-potency antimycotic activity in vivo. It is ironic that even replacement with benzimi-dazole, the original lead compound, exhibited very low effectivness. Exchanging one nitrogen with carbon (i.e., pyrazoles and piperazines) also resulted in less active, or even inactive,...

J1i IP

Which subsequently transforms to the irreversible complex EI*. On breakdown the antibiotic fragments (X + Y) regenerate the enzyme in active form. At concentrations of inhibitor , the formation rate EI depends on the K3 Ki ratio. Free enzyme levels, of course, depend on antibiotic levels and the values of K4 and K3 Ki. It is apparent that an effective inhibitor (i.e., a good drug) should have a low K4 and high KJIKi value. If this model is really valid, then it may help explain why inhibition...

Catecholaminergic Receptors

The organs innervated by adrenergic nerves (Fig. 9-6) can be stimulated experimentally by EP and NE with the same qualitative results as those obtained by nerve stimulation (see Table 8-1). Thus we speak of these and related drugs as being sympathomimetics. It is now generally accepted that the reaction between the adrenergic neurotransmitter NE and adrenoreceptive sites (adrenoceptors) on the effector organs is responsible for these effects. It became apparent early in the century that some...

Nhch2cnh2

Cumulative renal, hepatic, and, particularly, cardiac damage were soon recognized. Pentavalent antimonials, being less toxic, are probably safer and more effective. They may be viewed as derivatives of the antimonide ion Sb(OH) . Sodium stibogluconate (Fig. 7-9) can be prepared from Sb205 and gluconic acid in the presence of solubilizing NaOH solution. The exact structure and composition are not known, but are based on tartar emetic by analogy. Polymeric properties of antimonic acid makes...

O Nh

Believed to significantly involve ribosomal subunit interactions (Chapter 6). A possibility that Mg2+ may link the ribosome to the tetracycline via ribosomal RNA phosphate groups and thus negatively affect protein synthesis has been proposed (Franklin and Snow, 1989). Mg2+ and Ca2+ chelate with the 11,12 p-diketone system as well as the 12 a- and 3-hydroxyl groups and are the likely sites of such potential interactions.

Mh2

It is now established that susceptible cells are those containing an appreciable sterol content as a membrane component and that the polyenes bind to the membranes (probably the sterols in them) irreversibly. Fungal cell walls are not involved. Following the membrane-polyene complex formation and the resultant alteration in membrane permeability, a leakage of cellular components, beginning with small molecules such as K+, Na+, inorganic phosphate, urea,...

X

Hw 2-hydroytatwaienc acid n 1 Lac lactic acid 1 ' Val Valine the gramicidins, it is not of clinical utility. Ionophoretically, valinomycin exhibits selectivity for K+ transport, resulting in the release of H+ from the cell. It had been proposed that each valinomycin molecule forms a complex with one K+. Such well-defined crystallized complexes have been isolated and characterized by X-ray crystallography. An octahedral complex of one K+ coordinated with six oxygen atoms (from the C O groups of...

I

L -ala-D leu L -ala-D-v l-L - vbI-D-vbI-L try-D leu L try S 11 Gramicidin B, 11th amino acid L-phe Gramicidin C D-try Another of the many ionophore antibiotics studied extensively is the cyclic valinomycin containing 12 acid residues of alternating amino acids (peptide linkages) with hydroxy acids (ester linkages) in repeating but sterically alternating d and l, set in units of four. This compound exhibits growth inhibition toward gram-positive bacteria and some fungi. Like

Ct

Catylpyiidlnlum Chlorida Benzoltanlum Chlorida Surfactants, or surface-active agents, exist as cationic, anionic, and nonionic moieties, and share the property of lowering the surface tension of aqueous solutions and, except for the last-mentioned group, also exhibit detergency and antimicrobial properties to varying degrees. Cationic surfactants may be quaternary ammonium, sulfonium, or phosphonium compounds, where the ammonium group represents the most widely used compounds. They usually have...

R

Nucleosides, and other small molecules. In addition to having both hydrophilic (peptide) and hydrophobic (alkane) groups, these drugs also have cationic surface-active properties (see later). The antibacterial effects are therefore neutralized by anionic detergents such as soaps. Polymixins are not orally absorbed. Thus systemic infections by sensitive organisms are treated by intramuscular injections or intrathecally (e.g., spinal meningitis). Toxicities are primarily to the kidneys and...

Membrane Active Drugs

In the following discussion the way in which various drugs may act on cellular membranes, and in turn be modified by this action, will be considered. One salient fact must be kept in mind Membranes pose an osmotic barrier between the internal contents of the cell and its external environment. Thus most studies are concerned with the mechanisms that help to explain the transport of drugs, ions, and biomolecules across membranes. Drug transport mechanisms essentially occur in two stages. The...

Ezj

Coccal activity for the sulfonamide azo dye prontosil in mice. The rationale for screening sulfonamido (-S02NH2)- containing dyes for possible antibacterial activity was based on the known binding propensity of these dyes to wool fibers that are protein (fast dyes). Analogous strong attachment (covalent bonding ) was assumed likely to bacterial proteins. The drug was introduced into clinical medicine on the basis of successful animal experiments. The curious puzzle that prontosil had no effect...

H O H

The lincosaminides and chloramphenicol. *Chiral centers **or hemisuccinate. described in 1962 and was originally obtained from S. lincolnensis, although it now can be produced from other species as well. LM is active primarily against Gm+ organisms such as streptococci, staphylococci, and pneumococci. Gm- aerobic bacteria are generally intrinsically resistant. Because of a likelihood of an intestinal condition called pseudomem-braneous colitis, the major use for LM and its...

The Macrolides

The following discussion will briefly outline two categories of macrolide (large ring system) antibiotics the lactone macrolides that include clinically useful erythromycins and several related compounds and the ansamacrolides, the most prominent members being the rifamcyins. The macrolide lactone antibiotics are isolated primarily from the genus Streptomyces. Their antibacterial activity is mostly in the Gm+ spectrum. They are classified on the basis of the size of the macrocyclic lactone...

The Lincosaminides

This small group of antibiotics shares an alkyl bonded to a proline function at C-6 (Fig. 6-26). Only one compound, lin-comycin (LM), and a semisynthetic derivative are in clinical use. LM was first isolated and 35 U.S. generic name is rifampin. 36 Just as the hydroquinone in photographic developers does.

Bta

Allcylisopropylacetylurea (Sedormid) R - CH2 CHCH2. R' - (CH3)2CH. X - H Figure 12-10. Early and simple-structured sedative-hyponotics. These drugs are either obsolete (hedonal) or rarely used in the United States. Schmiedberg (1886) first reported that urethane (ethyl carbamate) produces rapid and deep narcosis in dogs. (The drug was subsequently used as a veterinary anesthetic.) More alkyl esters were soon introduced as hypnotics or anesthetics. For example, hedonal, which is more active than...

CI mm ClCl

2-N,N-diaIkyl derivative (oqpected product) (Chlordiazepoxide - oMained product) Figure 12-15. Discovery of benzodiazepines the synthesis of chlordiazepoxide. 2-N,N-diaIkyl derivative (oqpected product) (Chlordiazepoxide - oMained product) Figure 12-15. Discovery of benzodiazepines the synthesis of chlordiazepoxide. The lack of similarity of UV and IR spectra to the 2-dialkylamino or 2-chloromethyl derivatives indicated chemically that this compound was not a quinazoline. Further...

Hypolipidemic Hypocholesterolemic Drugs

The fact that even young men can develop atherosclerosis was reported following autopsies of German soldiers during World War I. However, it was a U.S. Armed Forces Institute of Pathology report toward the end of the Korean War (Enos et al., 1953) showing that young men (average age 22) had evidence of coronary heart disease (CHD) that made the medical profession take note of the epidemic that was CHD. The problem is still extensive in spite of considerable, but slow, progress since the 1950s....

Adca

O J N-L-COOH Penicillin Sulfoxide a Nitrosyl chloride-anhydrous formic acid, a diazotization mixture. b Bis-trimethylsilyl-urea-pyridine HBr. c R CH3 or C2HS. Figure 6-10. Synthetic aspects of cephalosporin precursors. produce the so-called ureidopenicillins (because of the urea structure). These have the most extended antibacterial spectrum thus far, particularly in the Gm- area, including P. aeruginosa. Acid stability of all three compounds is poor, making parenteral administration the only...

Rxs

Mitomycin Mechanism Action

Proposed carmustine degradation (Montgomery et al., 1967). carbonium ion the alkylating agent. The chloroethyl isocyanate can act as a carbamoy-lating agent, or, after decomposing to 2-chloroethylamine, become a second alkylating species. A more general scheme for mono-alkyl functional nitrosoureas is outlined in Figure 4-8. Decomposition, possibly initiated by hydroxide ion, affords an isocyanate and hydroxy 2-chlorethyl diazine, which spontaneously decomposes to the 2-chloroethyl...

Narcotic Antagonists

Prior to the early 1940s no satisfactory pharmacologic antidote for opiate overdoses and poisoning existed. Treatment was essentially the same as for other CNS and respiratory depressants (i.e., with CNS stimulants and supportive physical methods). Some antagonism to the respiratory depression of morphine had been achieved by replacing the N-CH3 group of codeine with an allylic function (-CH2-CH CH2) during the 1920s. This fact was subsequently utilized as a rationale for the introduction of...

About Xup Pills

Guinosine-S' G, -mido triphosphate (Gpp NH p) Although much detail at the molecular level is still not fully known, it is clear that the majority of effects seen as a result of catecholamine actions at -adrenoceptors are mediated via adenyl cyclase activation and the resultant increase of c-AMP within cells. Thus the excitatory cardiac effects or increased inotropic response are the result of Pi stimulation. P2 stimulation leads to inhibitory effects on smooth muscles. The correlation between...

Why Scillaren Is Preferable Than Dihitoxin

Digoxigenin, R'* OH Digitoxigeain, ' H R - sugars Digoxin (Lanoxin) Digitoxin (Crystodigin) R ' tri-digitoxose R tri-digitoxose late eighteenth century that its real medicinal value was recognized in the treatment of CHF (actually, the accompanying edema, or dropsy) by W. Withering in England. After a decade of study and use he wrote a treatise in 1785 on the use of foxglove for dropsy and other diseases. For the next 150 years digitalis was used in the form of decoctions, infusions, tinctures,...

The 8Aminoquinolines

In the late nineteenth century, Guttmann and Ehrlich (1891) reported a low level of antimalarial activity by the basic dye methylene blue (Fig. 7-6). This resulted from Ehrlich's early work with dye staining of microorganisms. Prompted by a World War I quinine shortage in Germany, synthesis research utilized this clue to find that dialkylaminoalkyl moieties, replacing one methyl group of the dye's diemthylamino function, intensified the activity. Introducing such groups into the quinolines,...

Other Antiprotozoal Drugs

Table 7-2 lists the various drugs that have been useful for a variety of protozoal diseases. It will be noted that several are indicated for more than one condition (e.g., pentamidine against leishmaniasis, trypanosomiasis, and pneumocystosis). Several of these not yet discussed will now be considered. Protozoa being single-celled are the most primitive members of the animal kingdom. There are probably 45,000 species known. It is fortunate that only some parasitize humans and higher animals....

BuspironeIs Anxioselectivity Possible

The question arises whether anxiolytic activity must always be accompanied by concomitant skeletal muscle relaxant and anticonvulsant activity as well as strong sedation. Can an anxioselective drug exist that will not interact significantly and additively with CNS depressant compounds, particularly alcohol More significantly, both from a medical and sociologic viewpoint, will it be possible to treat anxiety and stress without the added complication of potent sedative effects, dependency, and...

Y 2h2 ch3

Ing degrees of CNS stimulant properties. Table 1-5 illustrates the relative intensities of pressor activity of the ephedrines and their racemates. As will be seen in subsequent discussions, a difference in activity, even to the point of antagonism, between optical isomers of the same structure is not unique to the ephedrines. This represents rotational stability about the ethylenic bond produced by ip2-orbital-hybridized carbon atoms. Since free rotation about the carbon-to-carbon axis is not...

Binifibrate Clofibric

HDL high-density lipoproteins LDL low-density lipoproteins VLDL very-low-density lipoproteins. HDL high-density lipoproteins LDL low-density lipoproteins VLDL very-low-density lipoproteins. of atherosclerotic diseases, particularly CHD. Of course, there are other risk factors as well (e.g., hypertension and smoking). The medical consensus is now focused on the necessity for reductions in total fat, saturated fats, and cholesterol in the blood. There are still some disagreements as to the...

Drug Resistance

It is probably a relatively recent recognition that one of the great factors in shaping human history has been infectious disease. Almost whole populations may have disappeared from the map. Bubonic plague killed one-third of Europe's population in the fourteenth century. The first documented pandemic was in the early sixth century. It began in northeast Africa (Egypt and Ethiopia) and spread through Europe. It lasted 60 years and is estimated to have killed 100 million people. Smaller...

Ci

D ( - ) Pseudoephedrine L ( + ) Pseudoephedrine will differ by 180 degrees. Unlike an enantiomeric pair of isomers, cis and trans isomers differ in both physical and even chemical properties (e.g., pKa if X is a carboxyl group). Interactions with receptors will differ greatly, even to the point of no binding. This should not be surprising when considering that the distance between X and Y may not be the same in the two isomers. Examples abound among drug molecules where one isomer only exhibits...

Peptic Ulcer Disease

The main digestive substances secreted are the proteolytic enzyme pepsin (as the proenzyme pepsinogen) and hydrochloric acid to produce the low pH at which the enzyme functions.1 The critical nature of HC1 to digestion and ulceration has been acknowledged, but not understood, for decades. In fact, the old dictum clinicians went by and still do is no acid, no ulcer. Since the molecular basis of what are only beginning to be recognized as complex interacting mechanisms was not well understood,...

Ho

Synthesis and metabolism of serotonin. TH tryptophane hydroxylase AAD L-aromatic amino acid decarboxylase MAO monoamine oxidase ADH aldehyde dehydrogenase. (Broken arrow indicates possible aberrant pathway.) Decarboxylation by l-aromatic amino acid decarboxylase intraneurally (as does l-dopa) affords serotonin. Even though the same reaction occurs peripherally, this neurotransmitter, like DA and NE, does not cross the BBB. In a manner analogous to the catecholamines, 5-HT is taken...

Methine Butyrophenone

Table 12-12 outlines the sequence of molecular modifications that on first attempt produced a normeperidine propiophenone analog where analgetic potency exceeded that of morphine 100 times. Lengthening the chain by one CH2 produced a butyrophenone whose analgesia was still much higher than morphine, but, surprisingly, that also exhibited a low-level CPZ-like pharmacology in animal screens. Even more unexpected was that replacement of the 4-carboethoxy (ester) group with a simpler OH led to the...

Mj

Facile synthesis of atropine (from Robinson, 1917). and racemic tropic acid was determined by early 1868. The structure of tropic acid was later proved by synthesis. The structure of tropine presented difficulties, but was finally established and confirmed by synthesis by Willstatter (1901). It must be appreciated that before the days of UV, IR, NMR, and mass spectrometry total synthesis, when feasible, constituted the only way of absolutely establishing an organic structure. The...

Ch2ch2ch2nhch3

Second-generation antidepressants. Trade names in parentheses. *Withdrawn in 1987. monoamine, while cocaine and amphetamine which do are not particularly useful in treating depression. It may be reasoned that if the acute effect of TCAs and MAO inhibitors is to raise the amine levels and yet no symptom relief is discernible for the first 2 weeks of treatment that the amine levels per se are not really significant or that these compounds are achieving their results by a different...

Tlp

Sulfazethin (Glu - D, Ah - D) Isosulfazethin (Glu D, Ala - L) were obtained from various Gm- bacteria, including species from the genera Pseudomonas, Gluconobacter, and Acetobacter. All these monobactams contain the 2-oxoazetidine-l-sulfonic acid moiety (Fig. 6-13). To maintain the analogy to the previously discussed (i-lactam antibiotics, these new compounds may be viewed as derivatives of 3-aminomonobactamic acid. This natural monobactam had several shortcomings as a potential drug. It showed...

Tetracycline Extension Of Chromophore Elimination

Loss of H (together with C6-OH) Remove OH, CH3 or both CI, Br, N02, (CH,)2N-Little information available ClandCHj Inviolate zone including C-l Epimerizing a-OH or deoxy Inactive degradation product Active, more stable drugs Activity retained Decreased activity (compared to 7 substitution) Any change lowers or eliminates all activity Decreased activity 3 Also refer to structure in Fig. 6-23. 6 Relative to tetracycline. Figure 6-19. Tetracycline activity regions. Phenoldiketone system pKa 2 7.2...

Prostaglandins

The fact that PG-synthetase is present in the gut wall, which, therefore, also contains types E and F PGs, has been known for a long time. The gastric mucosa in particular secretes E series PGs into gastric juice. PGEs and possibly PGAs can inhibit histamine-stimulated HC1 secretion without diminution of mucosal flow. The ability to maintain the mucosal integrity and thus protect the gastric wall, which is a property now named cytoprotection, has been ascribed to PGEs. In fact, such PG-mediated...

Cpl

CHjO P CH CO, CH, O OH Metrifonate The acetylcholinesterase in schistosomes acts as an inhibitory neurotransmitter so that inhibition of the enzyme results in paralysis. The suckers holding the worm to the wall of the vein let go, and the parasite is swept out to the lungs with the blood flow. Shortly after oral administration of the drug, serum cholinesterase levels in the patient are essentially eliminated while erythrocyte levels drop by about three fourths. These take several weeks to be...

Dihydropteridine

Dihydropteridine Pyrophosphate

-SO-C6H4NH2-p, -S-S-C5H4-NH2-p, -CONH2, or even -P03H2 groups yielded compounds retaining some antimicrobial properties. Activity approached or exceeded the original sulfonamides in a few instances. Other pioneering studies to relate antibacterial activity to the degree of ionization pKa , and thus to structural parameters, were carried out. Increased activity was observed as the pKa value reached 6.7 and lessened again with further increases. With time, very active compounds outside this...

Chloramphenicol

This broad-spectrum antibiotic was originally obtained from S. venezuelae. Its spectrum includes Gm and Gm- bacteria, anaerobes in both categories, and rickettsiae. The drug is active against cholera, lymphogranuloma venereum, and psitacosis. It is particularly useful against typhoid fever and other systemic Salmonella infections. The main reason for the caution in using the drug today is the possibility of developing fatal aplastic anemia and other blood dyscrasias such as agranulocytosis. The...