Stereochemical Properties of Drug Molecules

Since drugs interact with optically active, asymmetric biological macromolecules such as proteins, polynucleotides, or glycolipids acting as receptors, many of them exhibit stereochemical specificity. This means that there is a difference in action between stereoisomers of the same compound, with one isomer showing pharmacological activity while the other is more or less inactive. In 1860, Louis Pasteur was the first to demonstrate that molds and yeasts can differentiate between (+)- and (-)-tartarates, utilizing only one of the two isomers. 

Therefore, complementarity between an asymmetric drug and its asymmetric receptor is often a criterion of drug activity. The effects of highly active or highly specific drugs depend more upon such complementarity than do those of weakly active drugs. Occasionally, the stereoselectivity of a drug is based on a specific and preferential metabolism of one isomer over the other, or on a biotransformation that selectively removes one isomer. Such 

Optical isomerism is the result of a dissymmetry in molecular suhstitution. The basic aspects of optical isomerism are discussed in various textbooks of organic chemistry. Optical isomers (enantiomers) may have different physiological activities from each other provided that their interaction with a receptor or some other effector structure involves the asymmetric carbon atom of the enantiomeric molecule and that the three different substituents on this carbon atom interact with the receptor. The Easson-Stedman hypothesis assumes that a three-point interaction ensures stereospecificity, since only one of the enantiomers will fit the other one is capable of a two-point attachment only, as shown in figure 1.13 for the reaction with a hypothetical planar receptor. However, it is reasonable to assume that receptor stereospecificity can also undergo a change when the receptor conformation is altered by a receptor-drug interaction. 

Diastereomeric drugs— those having two or more asymmetric centers—are usually active in only one configuration. Unlike enantiomers, which have identical physicochemical properties, the absorption, distribution, receptor binding, metabolism, and every other aspect that influences the pharmacological activity of a dmg are different for each diastereomer. 

Lehman et al. (1986) stated the definitions of stereoselectivity in the following manner the better fitting enantiomer (the one with higher affinity for the receptor) is called the eutomer, whereas the one with the lower affinity is called the distomer. The ratio of 

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