Significance of stereoisomerism in determining drug action and toxicity

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Pharmacy is a discipline of science that deals with various aspects of drugs. All drugs are chemical entities, and a great majority (30-50 per cent) of them contain stereocentres, show stereoisomerism and exist as enantiomers. Moreover, the current trend in drug markets is a rapid increase of the sales of chiral drugs at the expense of the achiral ones. In the next few years, chiral drugs, whether enantiomerically pure or sold as a racemic mixture, will dominate drug markets. It is therefore important to understand how drug chirality affects its interaction with drug targets and to be able to use proper nomenclature in describing the drugs themselves and the nature of forces responsible for those interactions.

Most often only one form shows correct physiological and pharmacological action. For example, only one enantiomer of morphine is active as an analgesic, only one enantiomer of glucose is metabolized in our body to give energy and only one enantiomeric form of adrenaline is a neurotransmitter.

One enantiomeric form of a drug may be active, and the other may be inactive, less active or even toxic. Not only drug molecules, but also various other molecules that are essential for living organisms exist in stereoisomeric forms, and their biological properties are often specific to one stereoisomer. Most of the molecules that make up living organisms are chiral, i.e. show stereoisomerism. For example, all but one of the 20 essential amino acids are chiral. Thus, it is important to understand stereochemistry for a better understanding of drug molecules, their action and toxicity.

Ibuprofen is a popular analgesic and anti-inflammatory drug. There are two stereoisomeric forms of ibuprofen. This drug can exist as (S)- and (R)-stereoisomers (enantiomers). Only the (S)-form is active. The (R)-form is completely inactive, although it is slowly converted in the body to the active (S)-form. The drug marketed under the trade names, commercially known as Advil®, Anadin®, Arthrofen®, Brufen®, Nurofen®, Nuprin®, Motrin® etc., is a racemic mixture of (R)- and (S)-ibuprofen.

(S)-Ibuprofen (R)-Ibuprofen

Active stereoisomer Inactive stereoisomer

In the early 1950s, Chemie Grunenthal, a German pharmaceutical company, developed a drug called thalidomide. It was prescribed to prevent nausea or morning sickness in pregnant women. The drug, however, caused severe adverse effects on thousands of babies who were exposed to this drug while their mothers were pregnant. The drug caused 12 000 babies to be born with severe birth defects, including limb deformities such as missing or stunted limbs. Later, it was found that thalidomide molecule can exist in two stereoisomeric forms; one form is active as a sedative, but the other is responsible for its teratogenic activity (the harmful effect on the foetus).

Sedative Teratogenic

Thalidomide stereoisomers

Sedative Teratogenic

Thalidomide stereoisomers

Limonene is a monoterpene that occurs in citrus fruits. Two enantiomers of limonene produce two distinct flavours: (—)-limonene is responsible for the flavour of lemons and (+)-limonene for orange. Similarly, one enantiomeric form of carvone is the cause of caraway flavour, while the other enantiomer has the essence of spearmint.

(S)-Fluoxetine (prevents migraine)

(S)-Fluoxetine (prevents migraine)

Fluoxetine, commonly known as Prozac®, as a racemic mixture is an antidepressant drug, but has no effect on migraine. The pure S-enantiomer works remarkably well in the prevention of migraine and is now under clinical evaluation.

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Responses

  • Tamara
    What is significance of streoisomerism in determining drug action?
    3 years ago
  • pertti
    How many streoisomerism has glucose?
    2 years ago
  • fethawi
    What is the significance and toxicity of stereoisomerism?
    17 days ago

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