Drugs stereoselective action

It has become abundantly clear that the stereoselective actions associated with the enantiomeric constituents of a racemic drug can differ markedly in their pharmacodynamic or pharmacokinetic properties [2-5]. These factors can lead to much concern, especially if a drug containing a potentially resolvable center is marketed as a racemic mixture. This situation is not invariably bad, but it is clear that a racemate should not be administered when a clear-cut advantage exists with the use of a resolved enantiomer [6]. An excellent discussion regarding the possible selection of a resolved enantiomer over a racemate, from both a practical and a regulatory viewpoint, has been provided by De Camp [7]. 

Jenner, R, Clow, A., Reavill, C., Theodoru, A., Marsden, C. D. Stereoselective actions of substituted benzamide drugs on cerebral dopamine mechanisms. J. Pharm. Pharmacol. 1980,32,39-44. 

Finally, it is important to remember that, in case of racemic drugs, it is important to resort to stereoselective methods to detect possible differences in the actions of the test compounds at the desired target and hERG channels. For instance, a recent study detected differences between (R)- and (S)-methadone [115]. 

The stereoselective nature of drug action should not be unexpected in view of the fact that all structures with which those compounds interact, receptors and enzymes. 

Many drugs exhibit stereoselectivity, with actions dependent on their spatial configuration. 

Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other. Similarly, drug transporters may be stereoselective. 

The significance of stereoselectivity in drug action in terms of drug-receptor interactions only becomes established when the more active isomers of groups of enantiomorphic pairs are shown to possess identical configurations. Stereochemical correlations within the methadone and isomethadone group are justified because the members of each possess chiral centers of similar nature (methadone type 29 isomethadone type 30) and subsequent... 

Vermeulen, N. P. E. (1986). Stereoselective Biotransformation Its Role in Drug Disposition and Drug Action, In Inrumative Approaches in Drug Research (A. E Harms, ed.), Elsevier, Amsterdam, pp. 393-416. 

Hence it is obvious that stereoisomeric influences as well as structural effects, play a major role in the production of the pharmacological profiles of medicinal agents. Variations noted in vitro that are related to the three-dimensional shape of a drug molecule originate primarily in stereoselective processes involved in the target site. In vivo variations related to stereochemical influences reflect selective interactions of the drug both at its site of action and in the various phases of biodisposition. 

The anticoagulant activity of warfarin is a classic example of stereoselective drug action. 5-warfarin in vivo is from two- to five-fold more anticoagulant than its i -enantiomer. This potency difference is coincidentally offset by the two-or five-fold greater plasma clearance of the distomer. 

Triggle, D. J. Stereoselectivity of drug action. Drug Discov. Today, 1997, 2, 138-147. 

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