Physiological effect, chirality

A different approach to making chiral drugs is asymmetric synthesis. An optically inactive precursor is converted to the drug by a reaction that uses a special catalyst, usually an enzyme (Chapter 11). If all goes well, the product is a single enantiomer with the desired physiological effect In 2001, William S. Knowles, Ryogi Noyori, and K. Barry Sharpless won the Nobel Prize in chemistry for work in this area. 

Chiral compounds are very important substances. Many natural products, medicinal compounds, and biomolecules exist as a single, optically active stereoisomer. Furthermore the opposite enantiomer or diastereomer may not have any physiological activity or may, in fact, have a detrimental physiological effect. There is therefore great interest in reactions in which only one stereoisomeric form of a compound is produced by a particular synthetic sequence. 

Many of these compounds have quite complex structures, often with multiple chirality centers. In addition, many of them are pharmacologically active that is, they have dramatic physiological effects on any organism that ingests them. For both of these reasons they have always interested organic chemists, and the determination of their structures and their syntheses continue to play an important role in the development of organic chemistry. 

A clear three-dimensional visualization of the means by which a receptor could differentiate between enantiomers was provided by Easson and Stedman in 1933 [25]. They proposed that three (b, c, d) of the four groups (a, b, c, d) linked to a chiral carbon atom were concerned in the process (either by normal valence forces, or by adsorptive or other forces). The receptor possessed three groups b, c and d for maximum physiological effect, the drug molecule must become attached to the receptor in such a manner that the groups b, c and d in the drug coincide respectively with b, c and d in the receptor. Such coincidence can only occur with one of the enantiomorphs and this consequently represents the more active form of the drug . The interaction (5) and non-interaction (6) were illustrated as follows ... 

Stereochemistry is of utmost importance to natural product synthesis, as different enantiomers of the same natural product can often produce very different physiological effects. Several methods can be used to generate enantiopure starting materials or to introduce chirality along the synthetic route, including asymmetric... 

Pharmaceutical compounds—drugs—are generally small to medium-sized organic molecules. Many are chiral. When this is the case, either a pure enantiomer or a racemic mixture may be used in therapy. Generally, the physiological effects of enantiomeric and racemic forms of a pharmaceutical compound are different. Drug development therefore involves the testing of both enantiomeric and racemic forms of candidate compounds. Before this can be carried out, the enantiomers of the compound of interest must be obtained and their stereochemistry defined. 

Most life processes involve chiral molecules and discrimination can be expected to be a common feature of the interactions. We refer here first to two special aspects, in the physiological responses of taste and odor. More than a century ago Pasteur noted that the (- -) and (—) forms of asparagine tasted differently — the former sweet, the latter insipid or almost tasteless. Since then, the often widely different physiological effects of (+) and (—) forms of various natural and synthetic compounds have been brought to light. 

The properties of two optical isomers differ only if the isomers are in a chiral environment—that is, an environment in which there is a sense of right- and left-handedness. A chiral enzyme, for example, might catalyze the reaction of one optical isomer but not the other. Consequently, one optical isomer may produce a specific physiological effect in the body, with its mirror image producing either a different effect or none at all. Chiral reactions are also extremely important in the synthesis of pharmaceuticals and other industrially important chemicals. 

Active ingredients in pharmaceuticals typically contain chiral atoms and their different enantiomers often show very different physiological effects. Therefore, the synthesis of many drugs requires asymmetric catalysis, with more and more biological methods and biocatalytic processes becoming used in the industry. 

Natural products of the general formula PhCH(OH)CH(NHMe)CH3 are isolated from Ephedra species and are called ephedrine and pseudoephedrine. They have various physiological effects, including uses as decongestants and appetite suppressants. Draw all four of the possible stereoisomers as Fischer projections, and assign the stereochemistry at each chiral center. Why do ephedrine and pseudoephedrine have different physiological effects Do the natural and unnatural isomers have different effects What is the relationship of these molecules to methamphetamine ... 

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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