The Revolution in Pharmacology

THE REVOLUTION IN PHARMACOLOGY D. W. WOOLLEY, Ph.D., M.D. (hon.)* Until very recently, the course ofprogress in the discovery ofnew drugs has depended on chance. The history ofpharmacology shows that the first member ofa series of useful agents has been picked up accidentally. The usual course ofevents cannot be illustrated better than by examination of the circumstances which led to the introduction of reserpine and other Rauwolfia alkaloids and ofchlorpromazine. The medicinal use in India ofextracts ofthe plant Rauwolfia serpentina dates back many centuries. Undoubtedly, its virtues, real or supposed, arose from the observation that ingestion ofparts of this plant was beneficial in certain diseases. After many hundreds of years this empirical information impressed itself on the Western world, and an intensive effort was begun about 1950 in Switzerland and in the United States to extract from this plant its active ingredient, to isolate it in pure form, and to find out what its chemical structure was. This was finally accomplished in 1954 with the establishment of the chemical structure of the most active constituent , viz., reserpine (1). Rauwolfia alkaloids were introduced into Western medicine for the treatment of high blood pressure. Quite incidentally it was found that these drugs also calmed excitable animals and human beings, and this observation led to widespread trials ofreserpine as a tranquilizing agent for mental patients. Medical practitioners of India had long ago noted this tranquilizing action ofthe plant and had used it on mental patients. The important point for the present discussion is that the introduction of these alkaloids into medicine was the result of chance observation. The chemical, biochemical, and pharmacological studies—¦ in other words, the scientific investigations—were predicated on these * The Rockefeller Institute for Medical Research. I74 D. W. Woolley · Revolution in Pharmacology Perspectives in Biology and Medicine · Winter 1958 chance discoveries. During these scientific studies, several new and apparently useful properties of the drugs were uncovered, but again quite by chance. The introduction of chlorpromazine illustrates another way that classical pharmacology has found new series ofuseful drugs. Reserpine was a plant alkaloid which was happened upon many hundreds of years ago. Chlorpromazine is a synthetic product ofthe organic chemist—first made quite recently but not for the purpose for which it is now best known. Its current widespread use arose from an unexpected property. Fourneau and Bovet had set out to synthesize a drug which would antagonize the pharmacological effects of adrenalin. This search led them unexpectedly in 1933 to the first antihistamine, i.e., to a drug which antagonized the action of histamine on animal tissues. Several years then elapsed, during which better and better antihistamines were found by the classical process of synthesizing and testing variations of this original first member of the series. In this way phenergan was discovered. It is one of the best antihistamines . All sorts ofvariations ofthe phenergan structure were then examined , and one turned out to have some unusual pharmacological properties. This was chlorpromazine. It was not simply an antihistamine, although it is that to some degree. It was used for a time to reduce the temperature of the body and to control nausea of pregnancy but has finally commanded attention because ofits tranquilizing effects on mental patients. These tranquilizing effects were observed recently quite by accident. We see from these two recent examples how chance provides us with useful drugs. Some skilful observer from antiquity provided us with a medicinal plant which he happened to find useful. We study this plant and isolate from it the active ingredient. We then determine its chemical structure . The next phase of the work is to modify this structure in order to build into the molecule additional desirable features. Although this last phase has not yet occurredwith reserpine, we can confidently expect it and can look to the experience with another useful plant alkaloid, viz., atropine , to see how developments may proceed. The structure of atropine has long been known and has been much modified by the organic chemist. He has collaborated with the pharmacologist to produce new and useful drugs. In this way many ofthe spasmolytic drugs, such as trasentine, were realized. They have some of the properties ofatropine, but some ofthe...