Enantiomers are a particular type of molecular isomer, sometimes termed optical isomers and even more rarely enantiomorphs. Molecular isomers (not to be confused with nuclear isomers) are chemical compounds with identical chemical formulae but with different molecular shapes. In some cases, the chemical groups can be completely different. In the case of enantiomers, the chemical groups are unchanged, but the arrangement of different groups around a central atom (generally a carbon atom) allows two potential structures that are mirror images of each other.
Molecular structures with the capacity to form enantiomers are sometimes referred to as chiral compounds as the two enantiomers are analogous to a pair of left and right hands.
This is very important in biology as much biochemistry, especially protein receptor and enzymatic activity will vary depending on the enantiomer. Indeed most natural organic compounds are only one of the two or more enantiomers that can exist for a molecule. Apart from glycine, the amino acids are chiral. Animals only use the levo forms and dextro forms can be toxic, by for example stereoselective deamination producing more peroxide radicals. Dextro amino acids are found in some bacteria.
Molecules that have only one chiral center will have two mirror image structures of each other. Molecules can have more than one chiral centre leading to several possible final structures.
Many common drugs come as enantiomers (see box). In some cases, the correct enantiomer is preferred, e.g. levobupivicaine has reduced cardiotoxicity in inadvertent systemic release. In other cases, there is no advantage so long as enough of the active drug is delivered.
When we factor in pharmacodynamics to the question of enantiomers we find that often drug toxicity can be related to enantiomers too. Thalidomide is an example—the R-enantiomer is a sedative, but the S-enantiomer is a teratogen and in the body, one enantiomer is converted to the other. Matters are very complex - this wasn't observed in animals beforehand, and only in rabbits subsequently. Another example is omeprazole, which is a 50:50 mix of enantiomers. However in the rat R-omeprazole is metabolised relatively safely, in man it is S-omeprazole that has the safer metabolism, less likely to have interactions, and in the dog it does not matter. So based on rat alone experiments esomeprazoles other enantiomer R-omeprazole might have been chosen as the son of omeprazole !
Most drugs now in development are pure enantiomers. This is generally a good thing, but does tend to add to the cost of synthesis and can make the biological precusor, such as Shikimic acid with a blockbuster like oseltamivir (Tamiflu) a potential controlling factor in production capacity. In fact there are other ways to get oseltamivar recently announced. These will not be used for a while in man, even if better, as biological equivilence of the end product will need to be proven. The example of sotalol reveals it can also be a bad thing to try only one enantiomer for clinical effect, as the enantiomers in a raecemic mixture can actually have complementary actions.
There are 3 conventions in use:
- R/S (R- and S-) (r- and s-) - the best and international standard for organic chemicals as it is by configerational labelling of each chiral centre on their ligands priority, according to the Cahn Ingold Prelog priority rules(CIP convention), based on atomic number. It has greater generality as it can cope with multiple chiral centres as are found in diastereomers such as of tartaric acid and the five and six carbon carbohydrates. The molecule is so oriented in space that the group with the lowest priority is pointed away from the observer. If the lowest priority substituent is assigned the number 1, and the highest 4, then the sense of rotation passes through 4, 3 and 2. A centre with a clockwise sense of rotation is a Rectus center and a center with an anticlockwise sense of rotation is a Sinister centre.
- D- and L- which are the old, but well known biochemical system based on glyceraldehyde as a reference molecule. The main advantage is that biologically active amino acids and carbohydrates are L- (Levo) rather than D-(Dextra). There is no fixed relationship with the R/S system but most biological L- compounds are S- (note you could change an S-amino acid to an R-amino acid derivative by changing an -OH group to an -SH). It is easy to confuse with the little l- and r- terms explained below. Such mixing of terms will only work predictably with glyceraldehyde (ie L-glyceraldehyde = l-glyceraldehyde = (+)-glyceraldehyde)
- (+)- and (-)-the oldest convention of all based on optical activity. This has no relation to the other two, and must be done by experiment ! When an isomer rotates the plane clockwise as seen by a viewer towards whom the light is traveling, that isomer is labeled (+). Take care as the symbol l- (for levorotatory) is the same as (+) and d- (for dextrorotatory) is the same as (-) but bear no necessary relationship to L- and D- respectively. So 9 of the 19 common L-aminoacids are d-aminoacids ((-)-aminoacids) !