Aspirin ( 2-(Acetyloxy)benzoic acid)

Salbutamol was synthesised from the naturally occurring substance, adrenaline.

Adrenaline

The problem with adrenaline was that it affected the alpha-receptors as well as the beta-receptors in the body. Thus as well as inducing bronchodilation, adrenaline leads to constriction of blood vessels and increased heart rate.

By adding another methyl group to the end of the molecule, a new drug, isoproterenol was made, that didn't act on alpha-receptors, only on beta-receptors.

Isoproterenol

Isoproterenol was introduced in the early 1960s; soon afterwards it was noticed that asthma mortality rates increased. One proposed cause for this phenomenon was that the beta1-receptor interaction of isoproterenol led to increased heart rate and thus cardiovascular problems. Another problem was the fact that it was extremely rapidly metabolised by the enzyme COMT to evolve a methyl ether.

To try and produce a drug not affected by COMT, a number of different compounds related to isoproterenol were synthesised and analysed. Salbutamol itself was synthesised by a research group as in the following 3-steps.

Step 1:

Step 2

Step 3

How Aspirin Works

When part of your body is hurt, the nerve endings release chemicals into the synapse, called prostaglandins, and working cells in the damaged tissues make these chemicals using an enzyme called cyclooxygenase 2 (COX-2). Aspirin inhibits this enzyme from making prostaglandins, in particular PGE2. The aspirin molecule enters the interior channel of the PGHS enzyme, and the molecule splits into two. The acetyl group binds to a site inside the channel and blocks arachindonic acid from the enzyme.

The above diagram shows this process with salicylic acid. Aspirin does exactly the same, apart from it sends its ethanoyl group (CH3-CO-) to the serene. It prevents the cell sending a 'pain' signal to the pain. However, aspirin also blocks COX1, which is responsible for thickening the stomach lining.

Sir John Vane discovered this in the '70s. To confirm his first predictions, he replaced the serene with alanine, which has no hydroxyl group. The cyclooxygenase activity of this enzyme was not affected by the aspirin, but when the amino acid, asparagine replaced the serine, the modified enzyme showed no COX activity during testing which suggests the ethanoylation of the enzyme prevents prostaglandin formation. Due to its long lasting and powerful effects, over 80 billion tablets are taken each year.

The search is now on for a 'super aspirin' that will selectively attack COX2 but leave the COX1, which protects the stomach lining. After research discovered that the 'tunnel' in COX1 was smaller than in COX2, the company Boehringer Ingelheim released the drug Meloxicam, which selectively inhibited the active sites in COX2. This was achieved mainly thanks to the research carried out in the '70s by Vane about how aspirin synthesised the enzymes and prevented the escape of COX (Later found to be COX1 and COX2). Meloxicam however, is no miracle as with it comes undesired side effects, such as dyspepsia and nausea. Even so, the race for a 'super-aspirin' is nearing the finishing line.

There is ongoing research into the causes and potential cures of asthma. Inspired by improving knowledge of asthma's biochemistry, more than 40 companies worldwide are investigating drugs to control the disease. Chemists are at the forefront of this worldwide operation. Salbutamol is effective for 4 hours but chemists at Glaxo later produced Salmeterol (a bronchodilator effective for 12 hours) through an even more drastic change to the group on the nitrogen in Salbutamol. Both Salbutamol and Salmeterol are very effective asthma treatments.

Due to on-going research, chemists have synthesised a new drug called Triamcinolone. Still in its testing phase, the table shows greatly increased success in comparison to Salmeterol.

According to the National Asthma Campaign, chemists in the UK are currently doing the following to improve the lives of people with asthma.

• the role of the primary care asthma nurse specialist in improving care for patients with poorly controlled asthma.

• a test for the respiratory function of young infants which can be used in the home.

• more effective treatments for people with severe asthma who are unresponsive to traditional medication.

• the use of specific asthma treatments that are better targeted at problem areas and reduce the possibility of side effects.

Open Book Examination

Adam Spencer