Historically, new medications have been discovered serendipitously; for example ‘milk of the poppy’ or opium, has been actively collected since prehistoric times and was described as far back as 1500 BC as a way to “stop a child crying”. Slightly more recently, manuscripts of Pseudo-Apuleius’s 5th century work from the 10th and 11th centuries refer to the use of wild poppy for inducing sleep and relieving pain. Likewise, Quinine was long collected from tree bark by the Quechus, who are indigenous to Peru, as a muscle relaxant before it made its way to Europe as the first effective anti-malarial.
In the 18th/19th centuries, growing scientific awareness led to breakthroughs in the treatment of diseases such as scurvy (Lind, 1763), vaccination against smallpox (Jenner, 1798) and control of basic infections by antiseptics (Semmelweis, 1861 and Lister, 1867). However, by the mid 19th century, treatment of many common ailments was still as dependent on superstition and tradition as it was scientific knowledge. This led the famous physician and poet Olivier Wendell Homes to denounce the entire accepted treatments of the time.
“I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be better for mankind – and all the worse for the fishes…”
O.W. Homes, 1860
The key moment in the modernization of medicine was in the coming together of three major industries of the 19th century. The science of biomedicine was in its infancy; pioneers such as Rudolph Virchow in Germany (cell theory), Rudolf Buchheim in Estonia (the bioassay) and Louis Pasteur in France (germ theory and immunization) were championing evidence based approaches to medicine. At the same time, the field of synthetic organic chemistry was advancing, with Lauder Brunton synthesizing perhaps the first small molecule therapeutic, Amyl nitrite, for the treatment of angina. Additionally, the explosion of the use of organic chemistry in the coal/tar industries allowed for improvements in basic techniques and eventually to standardized purification of natural products, such as morphine.
The pharmaceutical industry as we know it today, started with large chemical companies purifying natural products from fungi/microorganisms (penicillin, tetracyclines, streptomycin) and plants (vincristine, taxol). Improvements in synthetic chemistry led to the development of large chemical pipelines and ensured that chemistry was pre-eminent in drug discovery until the 1970s. Many of the drugs still used today (antihypertensives, antidepressants, antipsychotics) relied on this chemical based drug discovery. Rather than trying to understand the mechanism of action, biologists would simply design huge numbers of assays to test the biological activity of thousands of chemicals, until they found one that worked.
Target directed drug discovery
A shift in thinking occurred when the nobel laureate Paul Ehrlich tried to explain some species specific dyes he had discovered by arguing that different species had different “chemoreceptors”. He believed that as chemical dyes could specifically stain bacteria, these dyes could be exploited to create drugs that would only target certain bacterial strains. Ehrlich’s work triggered a race between chemical companies to create specific antimicrobials that could be administered internally without damage to the host organism. This lead to the discovery of Prontosil, the first commercially available antibacterial antibiotic, by scientists at Bayer.
Curiously, Prontosil had no biological activity in a test tube, but was highly effective at killing bacteria when administered to mice. Further work found that Prontosil was in-fact cleaved in the body to form sulfanilamide, the active compound, making it the first discovered pro-drug. This was a great victory for biology driven drug discovery, but a blow to Bayer, who couldn’t patent sulfanilamide as it had been used for years in the dye industry.
With the structure of sulfonamide known, biologists were able to find its target in the folic acid pathway. Bacteria synthesize folate to produce folic acid (vitamin B9), however eukaryotes get all their folate from their diet. Sulfonamides mimic a substance called PABA and compete for an enzyme responsible for folic acid synthesis. Targeting this pathway was a highly successful strategy for producing drugs, slight chemical modifications led to the development of the first oral hypoglycaemics and the first thiazide and loop diuretics. Further research into the folate pathway even led to the discovery of enzymes important in DNA synthesis and cell division, and eventually one of the first anti-cancer drugs 6-mecaptopurine.
From chemical to target-directed approaches
In 1901, Langley challenged the dominant hypothesis that drugs act at nerve endings by demonstrating that nicotine acted on the surface of muscles tissues even after degeneration of the severed nerve endings. In 1905 he introduced the concept of a receptive substance on the surface of skeletal muscle that mediates the action of a drug. He also postulated that these receptive substances were different in different species, citing the fact that nicotine-induced muscle paralysis in mammals was absent in crayfish.
Years later, Alquist defined adrenergic receptors as “hypothetical structures… affected by epinephrine”. Alquist then investigated the actions of related catecholamines on multiple functions in multiple species. The rank order of potency for all tissues and functions fell into one of two distinct patterns. He concluded that the affects of adrenergic receptors were mediated by two distinct receptors; “tentatively called alpha adrenotropic receptor and beta adrenotropic receptor”. Alquist’s critical breakthrough was that receptor types and subtypes defined their pharmacological properties, rather than the nature of observed physiological response.
Alquist’s work laid the foundation for the discovery of the first useful beta blocker, propranolol, by Sir James Black. This was both one of the very first blockbuster drugs, and the first example of a pharmacologically identified receptor deliberately targeted in a drug discovery project. Black went on to discover burimamide, the first H2 antagonist and first effective treatment for peptic ulcers, and open the field of receptor pharmacology as an approach to drug discovery.
Era of molecular biology
Since the late 1950s and early 1960s, molecular biologists have learned to characterize, isolate, and manipulate the molecular components of cells and organisms. These components include DNA, the repository of genetic information; RNA, a close relative of DNA whose functions range from serving as a temporary working copy of DNA to actual structural and enzymatic functions as well as a functional and structural part of the translational apparatus; and proteins, the major structural and enzymatic type of molecule in cells. Today, receptors have changed from being figments of a pharmacological scheme to discrete molecular entities. Receptors can now be isolated, labelled, cloned and expressed in other cells. These advances have had a radical effect on the drug discovery process and will form the basis of future posts.