Enantioselectivity of Drug Action

Many drugs are racemates, including 13-blockers, nonsteroidal anti-inflammatory agents, and anticholinergics (e.g benzetimide A). A racemate consists of a molecule and its corresponding mirror image which, like the left and right hand, cannot be superimposed. Such chiral ( handed ) pairs of molecules are referred to as enantiomers. Usually, chirality is due to a carbon atom (C) linked to four different substituents ( asymmetric center ). Enantiomerism is a special case of stereoisomerism. Non-chiral stereoisomers are called diaster-eomers (e.g., quinidine/quinine). 

Bond lengths in enantiomers, but not in diastereomers, are the same. Therefore, enantiomers possess similar physicochemical properties (e.g., solubility, melting point) and both forms are usually obtained in equal amounts by chemical synthesis. As a result of enzymatic activity, however, only one of the enantiomers is usually found in nature. 

In solution, enantiomers rotate the wave plane of linearly polarized light in opposite directions hence they are refered to as dextro - or levo-rotatory , designated by the prefixes d or (+) and 1 or (-), respectively. The direction of rotation gives no clue concerning the spatial structure of enantiomers. The absolute configuration, as determined by certain rules, is described by the prefixes S and R. In some compounds, designation as the D- and L-form is possible by reference to the structure of D- and L-glyceraldehyde. 

For drugs to exert biological actions, contact with reaction partners in the body is required. When the reaction favors one of the enantiomers, enantioselectivity is observed. 

Enantioselectivity of affinity. If a receptor has sites for three of the substituents (symbolized in B by a cone, a sphere, and a cube) on the asymmetric carbon to attach to, only one of the enantiomers will have optimal fit. Its affinity will then be higher. Thus, dexeti-mide displays an affinity at the musca-Lullmann, Color Atlas of Pharmaoology 

Inverse enantioselectivity at another receptor. An enantiomer may possess an unfavorable configuration at one receptor that may, however, be optimal for interaction with another receptor. In the case of dobut-amine, the (+)-enantiomer has af nity at p-adrenoceptors that is 10 times higher than that of the (-)-enantiomer, both having agonist activity. However, the a-adrenoceptor stimulant action is due to the (-)-form (see above). 

As described for receptor interactions, enantioselectivity may also be manifested in drug interactions with enzymes and transport proteins. Enantiomers may display different af nities and reaction velocities. 

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