The Racemate Has a Therapeutic Advantage over the Individual Enantiomers

Both enantiomers may contribute to the therapeutic effect though examples of chiral drugs exhibiting 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 experimental 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

(+)-Dobutamine - p-adrenoceptor agonist a-adrenoceptor antagonist

(-)-Dobutamine - p-adrenoceptor agonist a-adrenoceptor agonist

COOCH3

(S)-BayK8644 (activator of L-type Ca2+ channel)

COOCH3

(fi)-BayK8644 (antagonist of L-type Ca2+ channel)

COOCH3

(S)-BayK8644 (activator of L-type Ca2+ channel)

(fi)-BayK8644 (antagonist of L-type Ca2+ channel)

FIGURE 5.9 Examples of drugs where the eutomer and the distomer have the opposite biological activity.

FIGURE 5.9 Examples of drugs where the eutomer and the distomer have the opposite biological activity.

CO2H

CO2H

CO2H

(fi)-DCPG AMPA receptor antagonist no effect on mGlu8

(S)-DCPG No effect on AMPA receptor mGlu8 receptor agonist

FIGURE 5.10 Both (R)- and (S)-3, 4-DCPG have potential therapeutic value. However, the racemate is more potent as an antiepileptic agent.

the (S)-enantiomer has agonist activity at the mGluR8 receptor subtype of metabotropic glutamate receptors. Thus, combining an AMPA receptor antagonist with a mGluR8 receptor agonist leads to a potentiation of antiepileptic activity. For further details about glutamate receptors see Chapter 15.

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