Chirality in the courtroom – the trial of an athlete

2004

YEAR BOOK

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University College Dublin

Theresa Ahern*

Chirality in the courtroom – the trial of an athlete

A medal winner in a recent Olympic Games event was forced to forfeit a medal when a drug test gave a positive reading for Speed. The athlete denied knowingly taking the drug, the only defence being that medication was taken to help clear a cold before competing. The rules of the International Olympics Committee, IOC, state that 'an athlete is responsible for what turns up in a drug test, regardless of how it got there'. The evidence for this case requires an understanding of the chemistry behind Speed (a stimulant drug of abuse) and the cold medication, the effect of drugs on our bodies, and the standard methods of drug testing.

Figure 1. S-, R-methamphetamine

This case incorrectly implies an ominous connection between the medication and Speed, whereas the relationship can be explained in terms of a natural 3-D phenomenon known as chirality. The word chiral comes from the Greek word cheir meaning hand. When you hold a right hand up to the mirror, you see a left hand, but it is not possible to superimpose one on the other. In this way, our hands are said to be chiral. The general example of chirality in chemistry is a molecule containing a carbon atom with four different groups attached to it. This molecule is non-superimposable on its mirror image, and the mirror images are called enantiomers, labelled R and S.

Chirality is relevant to our competitor's case as the active ingredient in the medication, S-methamphetamine, contains a chiral centre and so has a mirror image, R-methamphetamine, that is known as Speed (Figure 1). R- and S-methamphetamine have identical physical and chemical properties in the absence of an external chiral influence – e.g. they have the same melting point, chromatographic retention time, and Nuclear Magnetic Resonance spectra as each other.

However, biological systems can recognise the members of a pair of enantiomers as different substances, and the two enantiomers will therefore elicit different responses. Why do enantiomers have different biological activities? In order to exert its biological action, a chiral molecule must interact with a chiral receptor, similar to a hand fitting into a glove. But just as a right hand can only fit into a right hand glove, so a particular enantiomer can only fit into a receptor site having the complimentary shape. The other enantiomer will not fit, like a right hand in a left glove, but may fit into a receptor site elsewhere in the body and cause an unwanted effect, or may even accumulate to potentially toxic levels in the body.

Not surprisingly, the Food and Drug Administration insists that a pharmaceutical company which wishes to market a drug as a mixture of enantiomers must establish the activity of both enantiomers and also show that the unwanted enantiomer does not cause any adverse effects. The search for efficient syntheses of enantiomerically pure compounds is an active area of research in both academic and industrial laboratories. Under normal laboratory conditions, when a chiral centre is introduced into a molecule, a mixture containing equal amounts of the two enantiomers is obtained.

My area of research focuses on the use of asymmetric synthesis to selectively prepare one enantiomer. This is achieved through the introduction of a chiral ligand – a bulky molecule that influences the formation of the new chiral centre. My work focuses on the synthesis of one new class of chiral ligands, and testing their efficacy in preparing enantiopure compounds. The basic design of my ligands is very promising, as they have selectively formed 97.5% of one enantiomer and only 2.5% of the other in an important synthetic transformation.

Figure 2. Drug testing GC

The standard method of chemical analysis is Gas Chromatography, GC for short. In this technique, each substance takes a unique specific time, called the retention time, to pass through the column. In drug testing, standard samples of drugs are run, as well as the urine samples, and the retention times of the peaks compared. Specific drugs can be identified and quantified easily. GC was used to analyse the competitor's urine sample, wherein a peak at the same retention time as Speed resulted in a positive drug test (Figure 2). Under standard GC conditions, there is no differentiation between enantiomers. However, if a chiral GC column is used, enantiomers then have different retention times. Thus, chiral GC would have been a more reliable method for differentiating between R- and S-methamphetamine (Figure 3). The R- and S-enantiomers fit into two different receptor sites in our bodies so, in taking the medication, the competitor did not experience any of the performance-enhancing effects of Speed.

Figure 3. Chiral GC

While a trial established that the competitor did not use the active enantiomer of a performing enhancing drug, the rules of the IOC required the medal to be forfeited. It is a salutary warning to athletes to exercise great care when taking any medication without ensuring that it is approved by the IOC.

*Theresa Ahern was one of the participants in AccesScience '04 held in UCD in May 2004. This is an edited summary of her presentation. She is a third year PhD student working with Professor Pat Guiry.

Contact: Theresa Ahern, Department of Chemistry, Centre for Synthesis and Chemical Biology,
Conway Institute, University College Dublin;
Tel: (01) 7162319; E-mail: [email protected]