Morphine functional groups

Figure 2.7. The role of functional groups in drag distribution, a Some functional groups in drag molecules that affect lipid solubility and membrane permeability, b Ampicillin (top) and its resorption ester bacampicillin (bottom). The pro-drag bacampicillin is cleaved to release ampicilhn after intestinal uptake, c Morphine (left) and heroin (right). The acetyl groups facihtate distribution into the central nervous system, where they will be cleaved off.

A number of common drugs contain the phenol functional group. These include paracetamol (pFCa 9.5), morphine (pKa 9.9) and levothyroxine (thyroxine) (pKa 10). Since these phenolic drugs are 50% ionised when the pH equals their pKa, it follows from the rule of thumb introduced in Chapter 1 that they will only ionise to approximately 1% at the pH of blood (7.4). See Figure 3.6. 

Replacement of the halogen atom of these compounds by other functional groups results in migration of the double bond and substitu-ont, a phenomenon that confused the early work on codeine and morphine. 

Opium contains a complex mixture of almost twenty-five alkaloids. The principle alkaloid in the mixture, and the one responsible for analgesic activity, is morphine, named after the Roman god of sleep—Morpheus. Although pure morphine was isolated in 1803, it was not until 1833 that chemists at Macfarlane Co. (now Macfarlane-Smith) in Edinburgh were able to isolate and purify it on a commercial scale. Although the functional groups on morphine had been identified by 1881, it took many more years to establish the structure of morphine and it was not until 1925 that Sir Robert Robinson solved the puzzle. Another twenty-seven years were to pass before a full synthesis of morphine was achieved in 1952. 

The first and easiest morphine analogues which can be made are those involving peripheral modifications of the molecule (that is, changes which do not affect the basic skeleton of the molecule). In this approach, we are looking at the different functional groups and discovering whether they are needed or not. 

To sum up, the important functional groups for analgesic activity in morphine are shown in Fig. 12.10. 

Up till now, we have considered minor adjustments of functional groups on the periphery of the morphine skeleton or drastic simplification of the morphine skeleton. 

The correct structure of morphine was proposed in 1925. Ultimate proof of its correct structure had to await its total synthesis, accomplished three decades later. The lack of the correct structure of morphine did not discourage the synthesis of several morphine congeners and derivatives by chemical reaction with the known peripheral functional groups, specifically the phenolic hydroxyl (C-3), and allylic alcohol (C-6), and the double bond (C-7-8) (Fig. 5-8). Among the derivatives introduced before 1930 and still in common usage today are codeine,6 ethylmorphine (Dionin), diacetylmorphine (heroin), hydromor-phone (Dilaudid), hydrocodone (Dicodid), and methyldihydromorphinone (Metopon). 

Heroin, the diacetate ester of morphine, does not occur in nature but can be synthesized from morphine. As shown in Figure 17.5, their structures differ in only one kind of functional group. Heroin is much more addictive than morphine and for that reason has no legal use in the United States. Codeine, a methyl ether of morphine, is one of the alkaloids in opium and is used in cough syrup and for relief of moderate pain. Codeine is less addictive than morphine, but its analgesic activity is only about one-fifth that of morphine. One of the most effective substitutes for morphine is meperidine, whose structure was identified in 1931, is now sold as Demerol. It is less addictive than morphine. 

Identify by chemical name the oxygen-containing functional groups in morphine, codeine, and heroin (see Figure 17.5). 

The physicochemical effect of the addition of two acetylester functional groups to morphine is to decrease molecular polarity, and thus increase lipid solubility and membrane permeability. Heroin is a strong base with a pfCa of 7.6 at 23°C and readily hydrolyzes to 6-acetylmorphine under various conditions. Heroin is especially susceptible to base-catalyzed hydrolysis, but will also hydrolyze in the presence of protic solutions including alcoholic and... 

Identify the functional groups in morphine and meperidine. Classify the amino group in these opiates according to type (that is, primary, secondary, tertiary, heterocyclic, aliphatic, or aromatic). 

In an extremely powerful technique, Dams et al. [540] separated 18 opiates and their derivatives (morphine, codeine, naloxone, hydrocodone, papaverine, dextromethorphan, noscapine, bupremorphine, methadone, heroin, thebacone, ethylmor-phine, 6-monoacetylmorphine, acetyldihydrocodeine, acetylcodeine, normethadone, normorphine, norcodeine) with baseline resolution in <12 min This was accomplished on a fast LC phenyl column 53 x 7 mm (2 = 280 nm) using a simple 100/0—>50/50 (at 10min)—> 0/100 (at 12min hold Imin) (90/5/5 water/ methanol/acetonitrile with 50 mM ammonium acetate)/(50/50 methanol/ acetonitrile with 50 mM ammonium acetate) gradient. The mobile phase components were adjusted to pH pp 4.5 with formic acid prior to use. The phenyl column was chosen ova- the conventional Cg or C g columns because of the increased selective interaction with analytes containing the planar phenyl functional group. Detection limits from 50 to 450ng/mL (analyte dependent) were reported. 

In 1925, the structure of morphine was correctly determined. This structure functioned as a lead compound and was modified to produce other compounds with analgesic properties. Early modifications focused on replacing the hydroxyl (OH) groups with other functional groups. Examples include heroin and codeine. Heroin exhibits stronger activity than morphine and is extremely addictive. Codeine shows less activity than morphine and is less addictive. Codeine is currently used as an analgesic and cough suppressant. 

Recall from Chapter 2 that a drug will bind with a biological receptor if the drug possesses a specific three-dimensional arrangement of functional groups, called a pharmacophore. For example, the pharmacophore of morphine is shown in red ... 

Many functional groups undergo glucuronidation, but alcohols and phenols are the most common classes of compounds that undergo this metabolic pathway. For example, morphine, acetaminophen, and chloramphenicol are all metabolized via glucuronidation ... 

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