Stereoisomerism and drug action in the nervous system.

One of the principle goals of pharmacology is an adequate and acceptable description of molecular dynamics of the interactions of drugs with cells and tissues. There are two essential components to this description, the structure of the drug and the structure of the macromolecule with which the drug interacts. To be adequate, any description must be three-dimensional, and therefore there is no further need for emphasizing the steric aspects of the structure of the drug or the macromolecule. Certain generalizations can provide guidance into the three-dimensional study of drugs and their interactions with biochemical molecules which can be summarized by the following simple ideas (1); the first is that two molecules cannot be in the same place at the same time; the second is that unlike charges between two molecules attract and like charges repel; and the third states that chemical processes depend upon molecular contact (" molecular fit") between substances or functional groups that are interacting. The stereochemical aspects of optical isomers are denoted by Fisher's nomen­ clature (0 or L) [see Eliel (2)], sequence notation (R or S) of Cahn et al (3), and the sign notation (+ or -) wherever possible. In Fisher's nomenclature the symbols 0 and L relate to the configuration of a standard substance. When a series of compounds have the same configurational symbol, their projection formulae may be written in a certain specified way. If this series of compounds are interrelated by chemical transformation or common precursor (4), their pharmacological parameters can be compared with the pharmacological para­ meters of the series of compounds of opposite configuration. The configuration of the asymmetric moiety with the optimal pharmacological activity may be written by Fisher's projection formula. Fisher's nomenclature is useful when it is applied to compounds with one asymmetric carbon; difficulties arise when it is applied to compounds with more than one asymmetric carbon. The sequence notation (3) is based on the actual three-dimensional formula of the compound to be named; and therefore it is self-consistent for the molecule in question and cannot be used to relate a series of compounds. For example, L( -)-alanine and L( -)-cysteine are related configurationally and have the same absolute configuration. According to sequence notation L( -)-alanine has S-configuration while L( -)-cysteine has R-configuration. A series of compounds with the same