Chiral Recognition in Biochemical Pharmacology: An Overview
The epoch-making work of Pasteur, van’t Hoff and LeBel was published in 1860 and 1874, respectively, and marks the creation of stereochemistry as we understand it (reviewed by Holmstedt 1990). The observation by Piutti (1886) that the two enantiomers of a
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Chiral Recognition in Biochemical Pharmacology: An Overview B. TESTA and 1M. MAYER
Dr. JOACHIM M. MAYER died in October 2001.
A. Introduction The epoch-making work of Pasteur, van't Hoff and LeBel was published in 1860 and 1874, respectively, and marks the creation of stereochemistry as we understand it (reviewed by HOLMSTEDT 1990). The observation by PIUTn (1886) that the two enantiomers of asparagine have different tastes is perhaps the first literature report of enantioselectivity in a biological effect. Organoleptic differences between enantiomers have been discovered ever since (GARDNER 1982). Around the end of the nineteenth century and the beginning of the twentieth century, a number of studies were carried out on differences in the biological effects of enantiomers, but it seems that the first clear proofs were provided by CUSHNY (see below). Not seldom, the artist's intuition anticipates scientific discoveries, and enantioselectivity is no exception. Indeed, Charles Lutwidge Dodgson, better known by his nom de plume Lewis Carroll, wrote the following in Through the Looking Glass and What Alice Found There published in 1871: Perhaps Looking-glass milk isn't good to drink ..." [Said Alice to her kitten]. Or madly squeeze a right-hand foot Into a left-hand shoe ..." [Sang the White Knight to Alice]. The first quotation applies to enantioselectivity at a macroscopic biological level, as discussed in Sect. B., whereas the second quotation encapsulates chiral recognition (Sect. C.). Such is the sequence of arguments in this chapter, which serves as a general introduction to most of the following chapters in this volume.
B. Enantioselectivity at Macroscopic Biological Levels The therapeutic activity of a drug can be broken down into two components, namely, what the drug does to the body (pharmacodynamics, PD), and
M. Eichelbaum et al. (eds.), Stereochemical Aspects of Drug Action and Disposition © Springer-Verlag Berlin Heidelberg 2003
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B. TESTA and
1M. MAYER
what the body does to the drug (pharmacokinetics, PK). This is classical if not trivial knowledge, but it is not always realized just how closely PD and PK are intertwined and can influence each other (TESTA 1987). Thus, pharmacodynamic actions may influence disposition, for example, by modifying blood flow, whereas absorption, distribution, metabolism, and excretion will affect the intensity, duration, and localization of pharmacodynamic effects. Perhaps the best known PK-PD interactions are the production of active or toxic metabolites, and the induction or inhibition of its own metabolism by a drug (autoinduction or autoinhibition). Yet despite such interactions, an exposition of stereoselectivity cannot consider all pharmacological events simultaneously, hence the sequential presentation of the following subsections.
I. Stereoselectivity in Drug Action and Pharmacodynamics 1. Pfeiffer's Rule and Eudismic Analysis The influence of chirality on pharmacological activities is illustrated in innumerable publications, an epoch-making work being th
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