Stereochemistry of drugs

The physiological properties of a drug are governed to a great extent by its stereochemistry. In recent years it has emerged that, in some instances, even optical isomers of a drug can have very different physiological effects. Since 

Drugs which have a geometrical isomer are relatively uncommon. 

An example of a drug with a geometrical isomer is the antidepressant zimeldine (Fig. 2.2). The lack of free rotation about the double bond ensures that the stereochemistry of this drug and and its isomer is different. Zimeldine is the only drug used. Other drugs which could also have geometric isomers of this type include amitriptyline and triprolidine. 

Optical isomerism of drug molecules is widespread. Many drug molecules only contain one or two chiral centres. A simple example is the naturally occurring neurotransmitter adrenaline. When a compound has no symmetry about a particular carbon atom the carbon atom is said to be a chiral centre. When a compound contains one or more chiral centres it is able to rotate plane-polarised light to the right (+) or the left (-). A chiral centre arises when a carbon atom has four structurally different groups attached to it. 

Using these rules we can assign the absolute configurations for adrenaline structures A and B. Placing the group of lowest priority behind the paper, in this case H. 

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Effect of pH on partitioning Drug stability Zero order degradation First order degradation Stereochemistry of drugs Geometrical isomerism... 

The SAR is also determined at the level of stereochemistry of interaction. In principle, three limiting situations can apply to the stereochemistry of drug-receptor interactions the enantiomers may not differ in activity the species may differ quantitatively or they may differ qualitatively. 

Caldwell, J., Winter, S. M., and Hutt, A. J. (1988). The Pharmacological and Toxicological Significance of the Stereochemistry of Drug Disposition, Xeno-biotica, 18 59-70. 

Stereochemistry of Drug-Nucleic Acid Interactions Its Biological Implications... 

Stereochemical aspects of drug action have been known for many decades. It is, however, only within the last couple of decades that emphasis has been placed on stereochemistry of drug disposition. The area that still needs far more attention is the effect of chirality on the physicochemical properties of drugs. Nevertheless, the present state of knowledge of the area... 

The stereochemistry of drugs and precursors can be vital in determining synthetic routes. Horvever, since enantiomers are nearly chemically identical, standard chromatographic methods cannot separate them. To effect a chromatographic separation of enantiomers, stereospecific interactions have to be incorporated. As described in Chapter 5, the use of chiral stationary phases is one method of discriminating enantiomers while capillary electrokinetic chromatography (MEKC) using chiral cy-clodextrins is another. Both of these protocols have been applied to methamphetamine and related compounds and precursors, substances that will be discussed in detail later in the chapter. 

Abdoul-Enein, H. Y Wainer, I. W. The Impact of Stereochemistry on Drug Development and Use Wiley-VCH New York, 1997. 

A. J. Hutt, J. O Grady, Drug chirality a consideration of the significance of the stereochemistry of antimicrobial drugs, J. Antimicrobial Chemother, 1996, 37, 7-32. 

Handedness is also important in organic and biological chemistry, where it arises primarily as a consequence of the tetrahedral stereochemistry of 5p3-hybridized carbon atoms. Many drugs and almost all the molecules in our bodies, for instance, are handed. Furthermore, it is molecular handedness that makes possible the specific interactions between enzymes and their substrates that are so crucial to enzyme function. We ll look at handedness and its consequences in this chapter. 

K. H. Dudley, S. B. Roberts, Dihydropyrimidase. Stereochemistry of the Metabolism of Some 5-Alkylhydantoins. Drug Metab. Dispos. 1978, 6, 133-139. 

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