Drug Discovery 101: The Story of Aspirin and Morphine

Drug Discovery 101: The Story of Aspirin and Morphine

A long but highly readable post that begins to explain how pharmaceutical companies bring drugs to the market. 

Originally shared by Ben Saward

Traditional Drug Discovery and the Story of Painkillers:

Pharmaceutical companies spend billions of pounds sterling here in the United Kingdom on developing drugs for sale. In 2012, £4.206 billion ($7.144 billion, conversation rate as of June 2014) was spent on this extremely important process known only to masses as research and development (R&D). The R&D expenditure here contributes to about one tenth of the global expenditure, while the US alone is responsible for half of the global expenditure.(1)

R&D is a critical component to any pharmaceutical company, being responsible for about a third of the company’s sales income. But what exactly is done with the huge sums of money that are pumped into ‘R&D’? The cost of research is deservedly high to ensure the safety and effectiveness of a product over a long period of time. Even now, showing that a drug is safe and effective may not be enough not recover the high cost of R&D. Companies may have to demonstrate the economic value of a drug in order to be reimbursed for treatment costs.

R&D is a very long process, with the average drug spending about 7 years between the start of trials and being approved for sale.(2) The entire process takes between 10 and 15 years, starting with a large number of potential products and ending with very few, usually only a single, viable drug.(3) 

Researchers use many different methods to find a potential drug targets. One method used is known as traditional drug discovery. It is not used very much in the modern industry but is a useful starting point for our journey through the R&D process, and is historically important as a lot of drugs that are now generic and well known to the public were discovered this way.

Traditional drug discovery turns to nature to find molecules that could potentially be used as treatments for various ailments. A striking example of this is the story of aspirin and also of morphine. Both ground willow tree bark and opium poppies have been used to alleviate pain in western countries since antiquity and in eastern cultures since prehistoric times respectively.

In traditional drug discovery, information like this is used and attempts to isolate specific molecules, the “active ingredients”, from a particular sample are made. In the case of bark willow, an extract that was found to be effective was salicin, a sugar derivative of salicylic alcohol. 

It was found that the body breaks down salicin into two compounds, glucose and salicylic alcohol, the latter of which is then oxidised to salicylic acid. It was found that salicylic acid alone caused pain relief. However, this compound was found to cause severe digestive issues such as bleeding, irritation and diarrhea. 

Aspirin is the compound that results from treating salicylic acid with an acylating agent such as acetic anhydride or acetyl chloride. It was first synthesised by the French chemist Charles Gerhardt in 1853. While there was no chemical theory of molecular structure in the 1850’s, treating the sodium salt of salicylic acid with acetyl chloride was later repeated by Schroder, Prinzhorn and Kraut, who correctly identified the chemical structure of aspirin.

Using the fact that salicylic acid could be used to alleviate pain, the German pharmaceutical company Bayer tested aspirin as a painkiller hoping it would demonstrate fewer side effects than salicylic acid. It was shown to be effective and showed less severe side effects, and we now have it on the market as a result.

The process of going from a natural product, such as salicin from willow bark, to a new chemical which is related to the original compound describes the process of traditional drug discovery perfectly. Scientists work without knowledge of specific biological pathways that cause symptoms such as pain to produce a drug. This stands in stark contrast to more modern techniques of drug discovery and design.

The mechanism of action of aspirin is still not fully understood, it is believed to suppress the production of an enzyme known as cyclooxygenase (COX) which is responsible for causing inflammation via the production of prostaglandins. It is believed to do this instead of directly inhibiting COX, but how it does that is currently unknown. The reason that salicylic acid and aspirin give the same relief of symptoms is that aspirin is broken down into salicylic acid by the body. (This means that aspirin is essentially a pro-drug for salicylic acid, a concept I shall introduce in another article)(4).

Morphine is an example of a compound that is taken directly from nature and sold on the market. It is one of the many components in Opium poppy extract that cause pain relief. These pain relieving compounds are known as the opioids and include naturally occurring molecules such as codeine and morphine as well as synthetic molecules such as heroin. They work by binding to the μ-opioid receptor in the central nervous system to release dopamine into the brain.

In some cases, like that of aspirin, it is much easier to produce the drug synthetically. This is why the study of natural and unnatural products is so fundamental to chemistry, particularly synthetic organic chemistry. Salicylic acid for the production of aspirin is made from the reaction with phenol with carbon dioxide under alkaline conditions (Kolbe-Schmitt reaction) followed by acidic workup conditions. This is then reacted with acyl chloride to give aspirin. These two reactions allow aspirin to be produced on an industrial scale with ease. Morphine is a much more complex molecule and so it is easier to extract it from poppies.

References:

(1) Association of the British Pharmaceutical Industry, http://goo.gl/ThIlUp

(2) Kaitin, Deconstructing the Drug Development process, http://goo.gl/JYtHhf

(3) Pharmaceutical Research and Manufacturers of America, http://goo.gl/MtYRgY

(4) Chemical Abstracts Service, http://goo.gl/DbnNRe

Various Wikipedia articles:

– http://goo.gl/g5M9Gh, Aspirin

– http://goo.gl/pVg7kP, History of Aspirin