Morphine, discovery

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

Mass spectrometry has been applied mainly in proteome research, but also in discovery and quantitation of neuropeptides that are involved in pain mechanisms, such as nocistatin, substance P, or verification of, for example, the structure of endogenous morphine in the central nervous system. Some proteomics studies of pain are aimed at the search for pain markers in cerebrospinal fluid, as it may reflect changes in brain and spinal cord functioning. Another research area concerns proteome analysis in cancer pain using spinal cord tissue and animal models. 

U-50488 has not only been a useful biological lead - its chemical structure, which is apparently unrelated to any of the classical morphine derivatives, has been used as the starting point for several drug discovery programmes. This has led to several publications and patents, particularly during the period 1989-1990, and these are discussed in this section. 

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. 

It is interesting to note that one of the founders of modern psychiatry, Kraepelin, listed only nine substances that were available for the treatment of psychiatric illness in the 1890s. These were opium, morphine, scopolamine, hashish, chloral hydrate, a barbiturate, alcohol, chloroform and various bromides. Later Bleuler, another founder of modern psychiatry, added paraldehyde and sodium barbitone to the list. Thus psychopharmacology is a very recent area of medicine which largely arose from the chance discovery of chlorpromazine by Delay and Deniker in France in 1952, and of imipramine by Kuhn in Switzerland in 1957. 

Much attention continues to be directed towards compounds of this class as a result of their now well-established analgesic properties in man, and the subject has been well reviewed [7, 180, 181]. The discovery that nalorphine was equi-potent with morphine in man, accidently revealed during studies of morphine-nalorphine mixtures [158, 182, 183], led to the clinical evaluation of other narcotic antagonists (both proven and potential) and has culminated in the development of the valuable drug pentazocine. Specific compounds of importance are considered below. 

In the past, a number of discoveries have been made in the absence of any knowledge about the receptors or ligands. One of the earliest examples of this kind is morphine (65) which was used for many years as an analgesic agent (as a constituent of opium, extracted from the poppy plant, Papaver somniferum) without... 

Although some efficacious drugs have been known for centuries, such as the antimalarial quinine first used in 1639, most important discoveries are of more recent origin. Smallpox vaccine was discovered around 1800, morphine in 1820, aspirin in 1894, and phenobarbital in 1912. But the discovery of the antibacterial activity of sulfur drugs in 1932 and penicillin in 1940 started the golden era of rapid expansion and discovery in the industry. Nearly all important drugs today have been discovered since 1940, some very recently. 

The discovery of morphine s analgesic activity by Sertumer in 1806 started a long series of studies of the alkaloids from the opium poppy, including morphine s first correctly postulated structure in 1925 and its total... 

Paracelsus, renowned physician and medical writer in the first half of the sixteenth century, called opium the philosopher s stone of immortality. In European medicine of the sixteenth and seventeenth centuries opium found wide use as an analgesic and sedative, although its abuse had become known from journeys of discovery to the Near and Far East. In the early nineteenth century a German pharmacist. Friedrich Sertumer. isolated the particularly active morphine from natural opium and this became widely used in military medicine as an analgesic and anesthetic in the latter half of that century. 

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 A -allyl derivative nalorphine (3-2) is prepared from A -demethylmorphine (3-1) by alkylation with allyl bromide [2]. The discovery that this compound proved to antagonize the activity of morphine in experimental animals led to the synthesis of the potent opioid antagonist naloxone (8-3), which is discussed below. Nalorphine (3-2), in marked contrast to the latter, does show some modest analgesic activity in humans. 

In the drug discovery stage, suitable sources are explored. Sources of drug molecules can be natural, e.g. narcotic analgesic, morphine, from Papaver somnifemm (Poppy plant), synthetic, e.g. a popular analgesic and antipyretic, paracetamol, or semi-synthetic, e.g. semi-synthetic penicillins. 

The first drug in this class was nalorphine (/V-allylmorphine). Nalorphine is equipotent with morphine but produced severe psychotomimetic activity, which precluded its use as an analgesic. Until the discovery of naloxone it was widely used for its antagonist properties in the treatment of opioid overdose. The dysphoric side effects of some of this class of drugs is thought to be due to binding to the non-opioid a receptor. 

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