Stereochemistry in Drug Design - Drug Design and Discovery - page 81

The drug dextropropoxyphene marketed by Eli Lilly has trade names rel ecting the different
activities of the enantiomers. Thus the (2 R , 3 S )-enantiomer, DARVON has analgesic properties
while the (2 S , 3 R )-enantiomer NOVRAD (Figure 5.7) is an antitussive.

5.4.3 D ISTOMER P OSSESSES H ARMFUL E FFECTS
In some cases, it is known that the distomer produces harmful or undesirable side effects. Thus, dex-
tromethorphan is used as a cough suppressant, while levomethorphan has antitussive properties but
it is also an opioid narcotic (Figure 5.8). The harmful teratogenic side effects of the ( S )-enantiomer
of thalidomide have already been discussed (Section 5.4).

MeO MeO

NMe NMe

H

H

Dextromethorphan
(cough supressant)

Levomethorphan
(narcotic)

O O

O O

H H

N N

NH HN

O O

O O

( R )-Thalidomide
(sedative)

( S )-Thalidomide
(teratogen)

FIGURE 5.8 Examples of drugs where the distomer possesses harmful effects.

5.4.4 T HE E UTOMER AND THE D ISTOMER H AVE THE O PPOSITE B IOLOGICAL A CTIVITY
It is sometimes observed that the enantiomers of a chiral drug may have opposite biological activity.
One example of this is (−)-dobutamine, which is an agonist at a-adrenoceptors while (+)-dobutamine
is an antagonist (Figure 5.9). However, (+)-dobutamine is 10-fold more potent than the (−)-isomer
as a b1-adrenoceptor agonist and is used to treat cardiogenic shock. The individual enantiomers of
the 1,4-dihydropyridine analogue BayK8644 (Figure 5.9) have opposing effects on l-type calcium
channels with the ( S )-enantiomer being an activator and the ( R )-enantiomer being an antagonist.

5.4.5 T HE R ACEMATE H AS A T HERAPEUTIC A DVANTAGE OVER THE I NDIVIDUAL E NANTIOMERS
Both enantiomers may contribute to the therapeutic effect though examples of chiral drugs exhibit-
ing this phenomenon are quite rare. We have reported that racemic 3,4-dicarboxyphenylglycine
(DCPG, Figure 5.10) displays a greater potency in preventing sound-induced seizures in an experi-
mental model of generalized epilepsy seizures than either enantiomer alone. The ( R ) enantiomer of
DCPG has antagonist activity at the AMPA receptor subtype of ionotropic glutamate receptors while