Here's an Experiment for You. Hold your hands out in front of you, your fingers extended and your palms facing away from you. Notice that your hands are mirror images of each other. Also notice that even though your hands are composed of exactly the same components – four fingers, one thumb – they are instantly distinguishable as being either your right or left hand.Now try and position your hands so that they become indistinguishable from one another – in other words, so that they exactly superimpose. You will quickly find that it can't be done – no matter how you position your hands, you can always tell your right hand from your left. Your hands have the special property of being non-superimposable mirror images of each other. Objects that possess this property are called ‘chiral' (pronounced ‘kyral'), this word being derived from the Greek word for ‘hand'.

 

 

More than you might think! Owing to their shape, certain molecules are chiral and can
therefore exist in two versions that are related to each other in the same way as a right and left hand. In fact, we can talk about the “handedness” of each version of a chiral molecule. In the laboratory, it is usually very difficult to prepare one handedness of a chiral molecule specifically and such synthesis normally results in an equal amount of both right-handed and left-handed forms.

However, this is not the case in nature, where it is found that either the righthanded or left-handed version of a chiral molecule predominates to the almost total exclusion of the other. For example, all of the naturally occurring amino acids that constitute the proteins in our bodies are left-handed. This has important consequences in the synthesis of therapeutic drugs.

In the same way as it is easier to shake a right hand with a right hand, rather than
with a left hand, two molecules of the correct handedness will interact much
more easily than molecules of the wrong handedness. Because nature consists
predominantly of molecules of one handedness, we find that drug molecules
having the correct handedness interact with specific molecules in the body and
are often much more effective than a mixture of the right- and left-handed
versions. In fact, the other handed form may even cause some unanticipated
side effects. Hence, the interest in the laboratory synthesis of specifically handed
molecules. So important is the science of developing a single isomer drug
that in the year 2001 the Nobel Prize in Chemistry was awarded to William
Knowles, Ryoji Noyori and Barry Sharpless for their work on chirally
catalysed reactions.

Chirality –
The word ‘chiral' comes from the Greek word ‘cheir', which means hand-like. It is a property exhibited by chiral molecules.

Chiral molecule -
A molecule, which has a chiral carbon atom (attached to four different groups) and is not superimposable on its mirror reflection.

Isomers –
Molecules, which have the same molecular formula i.e. same number and same type of atoms, but the arrangement of the atoms is different.

There are two types of isomers, structural isomers and stereoisomers.

Stereoisomers -
Molecules with the same molecular and structural formula but having a different 3-dimensional arrangement of atoms.

Enantiomers –
Non-superimposable mirror image stereoisomers

Racemate –
A mixture containing equal amounts of enantiomers.

 

 

In human airways, bronchoconstrictor responses are countered by epinephrine, which is released from storage sites within the suprarenal glands. Endogenous epinephrine – (R)-epinephrine – is a pure single isomer. (R)-epinephrine interacts with the ß2-adrenoceptor, activating adenylyl cyclase and thereby increasing intracellular concentrations of 3',5' – cyclic adenosine monophosphate (cAMP). In the airways, increased concentration of cAMP relaxes bronchial smooth muscle and preempts contraction of hyperresponsive airways; increased concentrations of cAMP also inhibits the release of inflammatory mediators from mast cells and eosinophils.

Synthetic compounds like ß 2-agonists, which are structurally similar to (R)-epinephrine are expected to mimic its actions. However, all marketed ß 2-agonists (terbutaline, salbutamol, salmeterol, formoterol, bambuterol) are racemates, composed of a 50: 50 mixture of the R-isomer (an analogue of epinephrine) and an S-isomer (an anti-analogue of epinephrine).

Salbutamol, the most widely used inhaled bronchodilator, which has a potent smooth muscle relaxing property, exists as a racemic mixture. It is the R-isomer (levosalbutamol) that provides the therapeutic benefit, while the S-isomer has been considered to be inert. However, recent evidence has suggested that this may be incorrect. Experimental and clinical studies have revealed that the S-isomer of salbutamol may cause a paradoxical intensification of airway obstruction, especially when chronic excessive doses are employed.

This logic provides the basis for levosalbutamol, the single-isomer form of racemic salbutamol.

 

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2. J. Allergy Clin Immunol 1999; 104: S31-41,
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4. R.Pauwels & P.Byrne, Beta2 – Agonists in Asthma Treatment, Marcel Dekker: 1-16