Codeine discovery

In addition, morphine has served as a point of departure for the discovery of many medically usefnl derivatives. These inclnde codeine, a pain reliever and cough suppressant, levophanol, an orally active analgesic (morphine is not active when given orally and is nsnally given by injection), and many other modem and highly potent opiate analgesics. 

The adventitious discovery, in prehistory, of the analgesic soporific and the euphoriant properties of the dried sap from the flower bulb of the poppy, papaver somnifemm, has been treated too often elsewhere to warrant repetition. By the nineteenth century organic chemistry had advanced far enough so that the active principle from opium had been isolated, purified, and crystallized. Increasing clinical use of this compound, morphine (1-1), and its naturally occurring methyl ether codeine (1-2) disclosed a host of side effects, the most daunting of which was, and stUl is, these compounds propensity for inducing physical dependence. 

The opium alkaloids codeine and morphine served as models for the synthesis of naloxone, an important analog used to treat and diagnose opiate addicts, and also led to the discovery of endogenous opioids (enkephalins and endorphins) (see Chapter 47). Similarly, A9-tetrahydro-cannabinol (THC), the component of Cannabis sativa responsible for the central nervous system (CNS) effect, has also been found to reduce nausea associated with cancer chemotherapy (see Chapter 18). 

Opium contains more than 20 distinct alkaloids. In 1806, Sertiirner reported the isolation of a pure substance in opium that he named morphine. The discovery of other alkaloids in opium quickly followed that of morphine (codeine by Robiquet in 1832 and papaverine by Merck in 1848). By the middle of the 19th century, the use of pure alkaloids rather than crude opium preparations began to spread throughout the medical world. 

In recent years there has been a major research effort, so far without success, to produce potent, centrally acting analgesics that do not have an abuse potential. The discovery of various types of opioid receptor, which may have different effects on central neurotransmitter function, may ultimately lead to the development of such a drug. In the meantime, the most widely used opioids, for example morphine, heroin (also called diacetylmorphine) and codeine are therapeutically effective but are liable to be abused and produce dependence. The structure of some of the morphine-like analgesics and their antagonists are shown in Figure 15.2. 

Heroin was first synthesized from morphine over a century ago. Since then, it has become one of the most abused substances. Research into why it produces such powerful effects has led to the discovery of specific opiate receptors and endogenous opioids (enkephalins and endorphins). These peptides appear to be neurotransmitters involved with the sensation of pain and pleasure. A number of opiates and synthetic opioids are available and can lead to dependency, including morphine, heroin, propoxyphene (Darvon), methadone, meperidine (Demerol), pentazocine (Talwin), hy-dromorphone (Dilaudid), oxycodone (Percodan), and hydrocodone (Vicodin, Damason-P), and codeine. 

In the discovery phase, metabolite identification is usually performed with a combination of in vitro and in vivo experiments using samples from different species in order to compare metabolite exposures. The structural identification of major circulating metabolites formed in nonclinical animal models as well as the metabolites formed in human in vitro systems is needed for the metabolites to be synthesized and their pharmacological activities and/or toxicological implications to be determined [25], In addition, metabolite identification can lead to the discovery of candidates with satisfactory clearance/PK properties and/or improved safety profile. Following are some examples of metabolites that were later developed as drugs desloratadine from loratadine, acetaminophen from phenacetin, morphine from codeine, minoxidil sulfate from minoxidil, fexofenadine from terfenadine, and oxazepam from diazepam. 

It was not until the late 18th and early 19th centuries that an analytical investigation of the active components of medicinal plants and herbal remedies was pursued. This resulted in the discovery of alkaloids such as atropine, morphine, codeine, and papaverine, which eventually became the major constituents of many modem analgesic and cardiac medicines. The discovery of aspirin (from Willow bark), the cannabinoids (from cannabis sct- ya), and digitalis (from foxglove leaf) also came many years, in some cases thousands of years, after these remedies were being used for pain relief, sedation, and dropsy (5-9). 

Papaver somniferum Papaveraceae (opium poppy) has been used as an analgesic since 3000 BC [26]. The opium latex contains many alkaloids, including codeine, thebaine, papaverine and morphine - its main analgesic constituent [27]. Although morphine has found large clinical use, its analgesic mechanism was first elucidated only with the discovery of both endogenous peptide opioids (such as enkephalins, dynorphins, endorphins and nociceptin) and the opioid receptors, p, 8, k... 

The discovery of morphine marked the begiiming of organic alkaloid chemistry, and the further analysis of papaver alkaloids proceeded quickly. There are over 50 papaver alkaloids in all, nitrogenous organic bases, but they can be divided into two major classes of papaver alkaloids - the isoquinolines and phenanthrenes. The phenanthrenes are the most medically significant, with morphine, codeine, and thebaine acting as important opioid agonists. 

One such technique, called lead modification, enables scientists to identify the portion of a compound responsible for its medicinal properties and then to design similar compounds with better properties. We will see an example of this technique, specifically, where the discovery of morphine led to the development of a whole family of potent analgesics (codeine, heroin, methadone, and many others). 

The next correlation was found in Scotland where Crum Brown and Fraser (1869) made a major discovery. They showed that several alkaloids, when quaternized, lost their characteristic pharmacological properties (many of them spasmogenic or convulsant) and acquired the muscle-relaxing powers of tubocurarine (2.6) (itself a quaternary amine), whose site of action had been shown to lie at the jimction between nerve and voluntary muscle, a few years earlier, by Claude Bernard (1856). Strychnine, bruceine, thebaine, codeine, morphine, nicotine, atropine, and coniine were quaternized into curarimimetic substances, by reaction with methyl iodide. The Scottish authors wrote There can be no reasonable doubt that a relation exists between the physiological action of a substance and its... 

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