Discovery of Morphine

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... 

Ibid., pp. 549-571. Details on Serturner s discovery of morphine are available in Rudolf Schmitz, Friedrich Wilhelm Sertilrner and the Discovery of Morphine, Pharm. Hist. 27 (1985) 61-74. 

The discovery of morphine by Serturner (1809—1817) stimulated an enormous activity in the field of plant products and most alkaloids still used today were found during the first half of the last century. The years to follow were not so productive, ephedrine being isolated in 1887 and scopolamine in 1888, and of all the alkaloids found in the first half of the 20th century, only the ergot alkaloids and (to some limited extent) lobeline from Lobelia inflata (Campan.) have found use in human therapy. 

From the beginnings of alkaloid research (from the discovery of morphine) to today, one of the most interesting questions has been and remains to be the function of alkaloids. In particular, the external function of alkaloids has... 

Before the discovery of morphine the existence of organic bases had not been suspected. Sertiirner (1817) showed that morphine forms salts with acids. Gay-Lussac then caused Robiquet to repeat and confirm the experiments, and before 1820 Pelletier and Caventou discovered strychnine, brucine, quinine, cinchonine, and veratrine. 

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). 

It was as a result of this 1817 paper that Sertumer s fame became assured, not only as the discoverer of morphine (1) but also as the founder of the whole field of plant alkaloids and their chemistry for brief accounts of the discovery of morphine, see Lockemann (1924, 1951) and Coenen (1954). Sertumer clearly understood that his new substance morphium was a plant alkali rather than an acid, as active principles in plants were up until then thought to be. The term alkaloid for such substances was introduced by Meissner (1819), because he considered that they differed greatly in many of their properties from true alkalis. Derosne s product was probably a mixture of morphine (1) and noscapine (narcotine) (2). 

Klockgether-Radke, A.P. (2002) F.W. Serttirner and the discovery of morphine. 200 years of pain therapy with opioids. Anaesthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie, 37,244-249. 

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. 

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 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. 

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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