The human dopamine D4 receptor gene (DRD4) contains a large number of polymorphisms in its coding sequence. And DRD4 polymorphic variants associate with numerous behavioral individual differences and some neuropsychiatric disorders.
The dopamine theory of schizophrenia shows that hyperactivity of the brain dopamine (DA) system leads to disorder. Previously, studies show a correlation between DA D2 receptor affinity and the efficacy of antipsychotic agents. there are wide variations in individual responsiveness to D2 receptor antagonists and liability to side effects. This means other receptors and/or mechanisms may be involved.
Also, the atypical antipsychotic agent Clozapine. It has a higher affinity for D4 receptors than for D2 receptors. As a result, the D4 receptor may be a good target for schizophrenia research.

In this article, we will introduce an orally active and selective D4 dopamine receptor antagonist, PD 168568.

PD168568 has a high affinity for the D4 dopamine receptor with a Ki of 8.8 nM. It exhibits a Ki value of 1842 nM for the D2 dopamine receptor. In rats, PD168568 has the ability to inhibit amphetamine-stimulated locomotor activity.

Because PD168568 has the greatest affinity for the D4 receptor. Researchers chose to separate its enantiomer. The absolute configuration of PD 172939 is determined to be R from the X-ray structure. Additionally, PD 108635 is the S-form. Both of them are potent  D4 receptor antagonists. The enantiomer of PD168568 also exhibits antipsychotic activity in vivo. The enantiomer PD172938 shows the highest D4 (Ki=42 nM) and 5HT-2 (Ki=36.4 nM) affinity in this test. What’s more, PD 172938 also inhibits amphetamine-stimulated locomotor activity in the rat.

In conclusion, a series of D4 ligands are introduced in this article. PD168568 and its enantiomer inhibit locomotor activity in the rat, indicating possible antipsychotic activity. These compounds have the potential for mental diseases research, including schizophrenia.


[1]. Belliotti TR, et al. Bioorg Med Chem Lett. 1998 Jun 16;8(12):1499-502.