activity of the eutomer and distomer is called the eudismic ratio; the expression of the
eudismic index is
In a series of agonists and antagonists (for definitions, see section 2.4), the eudismic
affinity quotient can also be defined as a measure of stereoselectivity. Because of wide-
spread misconceptions, the distomer of a racemate is often considered “inactive” and of no
consequence to pharmacological activity, an idea reinforced by the fact that resolution (i.e.,
separation) of racemates is economically disadvantageous. In the 1980s, Ariëns and his
associates (Ariëns et al., 1983; Ariëns, 1984, 1986) published a series of influential books
and papers that showed the fallacy of this concept and pointed out the necessity of using
pure enantiomers in therapy and research; thankfully, this message has now been learned.
The distomer should therefore be viewed as an impurity constituting 50% of the total
amount of a drug—an impurity that in the majority of cases is by no means “inert.”
Possible unwanted effects of a distomer are as follows:
- It contributes to side effects.
- It counteracts the pharmacological action of the eutomer.
- It is metabolized to a compound with unfavorable activity.
- It is metabolized to a toxic product.
However, there are instances in which the use of a racemate has advantages; sometimes
it is more potent than either of the enantiomers used separately (e.g., the antihistamine
isothipendyl), or the distomer is converted into the eutomer in vivo(the anti-inflammatory
drug ibuprofen).
Admittedly, the separation of enantiomers is often difficult and expensive. However,
now that we are in the 21st century, the need for optically active drugs capable of stere-
ospecific interactions with drug receptors is a recognized prerequisite in drug design.
1.4.3 Geometric Isomers of DrugsCis/transisomers are the result of restricted rotation along a chemical bond owing to
double bonds or rigid ring systems in the isomeric molecule. These isomers are not mirror
images and have very different physicochemical properties, as reflected in their phar-
macological activity. Because the functional groups in these molecules are separated by
different distances in the different isomers, they cannot as a rule bind to the same recep-
tor. Therefore, geometric isomerism as such may be of interest to the medicinal chemist.
In biological systems, there are a number of examples of the importance of cis/trans
isomerization. The human eye contains one of the most important examples. Rod cells
and cone cells are the two types of light-sensitive receptor cells in the human retina. The
three million rod cells enable vision in dim light; the 100 million cone cells permit
colour perception and vision in bright light. Within the rod cells, 11-cis-retinal(1.12)is
converted into rhodopsin a light-sensitive molecule. When rod cells are exposed to
light, isomerization of the C11–C12 double bond occurs, leading to the production of
atrans-rhodopsin, called metarhodopsin, that contains all-trans-retinal(1.13). This
cis/trans isomerization of rhodopsin leads to a change in molecule geometry, which in
DRUG MOLECULES: STRUCTURE AND PROPERTIES 39EI=log affinityEu−log affinityDist (1.4)