Stereospecificity, drug-receptor interactions

Since the ir value is constitutive, the stereospecific nature of hydro-phobic bonding for drug-receptor interactions can be delineated by regression analyses with the tt values of substituents separately for each position of the congeners. Thus, the substituent effect on the emulsin hydrolysis of substituted phenylglucosides has been nicely delineated by analyzing kinetic constants separately for meta and para isomers. The meta substituents play no hydrophobic role in the enzyme-substrate complex formation 24). 

Admittedly, the separation of enantiomers is often difficult and expensive. However, now that we are in the 21st century, the need for optically active drugs capable of stereospecific interactions with drug receptors is a recognized prerequisite in drug design. 

It seems likely that continuation of the study of partition coefficients will provide a great deal of Information about some of the factors involved in hydrophobic interactions. It does not seem likely that this approach will provide a great deal of information about the detailed mechanisms of stereospecific drugs interacting with stereospecific receptors. 

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. 

The bioactivity of a drug is the result of interaction with a biological receptor, a protein molecule with a binding site that is also chiral and stereospecific. The interaction of the D isomer of a drug with a chiral receptor site will differ from the interaction of the L isomer with that site. 

Answer Only one of the two enantiomers of the drug molecule (which has a chiral center) is physiologically active, for reasons described in the answer to Problem 3 (interaction with a stereospecific receptor site). Dexedrine, as manufactured, consists of the single enantiomer (D-amphetamine) recognized by the receptor site. Benzedrine was a racemic mixture (equal amounts of D and l isomers), so a much larger dose was required to obtain the same effect. 

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