Stereoisomers drug action

Chromatographic resolution of enantiomers, including the indirect approach, can be used in several different types of applications. The recent surge of interest (8-12) in the stereochemical aspects of drug action and disposition has been accompanied by a rapidly increasing need for synthetic and analytical methods for drug stereoisomers. Regarding analyti-... 

In spite of the move towards single stereoisomer products, the number of agents currently available as racemates is considerable, and for the majority of these relatively little is known with respect to the pharmacodynamic, pharmacokinetic, or toxicological properties of the individual enantiomers present in such mixtures. This chapter is not intended to be an exhaustive compilation of stereoselectivity in drug action but aims to provide an overview, illustrate some of the complexities that may arise, and indicate the significance of stereochemical considerations in pharmacology. More detailed evaluation of individual classes of drugs are presented in Chaps. 6 and 7. 

The related agents paroxetine and sertraline (Fig. 11) contain two centers of chirality in their structures, but both are marketed as single stereoisomers. The latter agent is interesting because the stereochemistry of the molecule has a marked influence on the selectivity of drug action (Table 2). In the case of the irons isomers, the (- -)-enantiomer is a potent inhibitor of the uptake of serotonin, dopamine, and noradrenaline, the (—)-enantiomer being relatively selective for inhibition of noradrenaline uptake. In contrast, with the cis isomers, a separation of activity occurs with the (- -)-15,45-stereoisomer, sertraline, retaining potent serotonin uptake inhibition activity [87,88]. The selectivity of action, expressed as a concentration ratio for the inhibition of dopamine and noradrenaline... 

An interesting example of the above difference is l-DOPA 4, which is used in the treatment of Parkinson s disease. The active drug is the achiral compound dopamine formed from 4 via in vivo decarboxylation. As dopamine cannot cross the blood-brain barrier to reach the required site of action, the prodrug 4 is administered. Enzyme-catalyzed in vivo decarboxylation releases the drug in its active form (dopamine). The enzyme l-DOPA decarboxylase, however, discriminates the stereoisomers of DOPA specifically and only decarboxylates the L-enantiomer of 4. It is therefore essential to administer DOPA in its pure L-form. Otherwise, the accumulation of d-DOPA, which cannot be metabolized by enzymes in the human body, may be dangerous. Currently l-DOPA is prepared on an industrial scale via asymmetric catalytic hydrogenation. 

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. 

The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability (see below). 

In the past, pharmacokinetic and pharmacodynamic investigations of chiral drugs have neglected the influences of stereoisomerism. This is primarily a result of the lack of stereospecific analysis procedures. Nonstereospecific assays give pharmacokinetic and pharmacodynamic information which represents a complex combination of the characteristics of the separate stereoisomers. With the advent of stereospecific analysis procedures a better understanding of drug kinetics and action as possible. 

The. stereochemistry of vitamin A and related compounds is complex, and a complete. stereochemical analysis is beyond the. scope of this chapter. A brief. summary of some stereochemical features is prc.scnied here as the basis for the characterization of the biochemical actions exerted by this vitamin. Tlte study of the structural relationships among vita-ntin A and its stereoisomers has been complicated by the common use of several numbering. system.s. as. shown below. The first numbering sy.stem (A) is the one currently recommended by the International Union of Pure and Applied Chemistry (lUPAC). The second sy.stem (B) places emphasis on the conjugated tt. system, while the third (C) is used by the USP Dictionary of USAN and International Drug Names. 

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