D1 and D2 dopamine (DA) receptors play important roles in terms of their neuroanatomical localization and cellular neurobiology.
However, any behavioral role for the D4 receptor remains poorly understood. Additionally, it may due to a paucity of agonists and antagonists showing meaningful selectivity for this site. And the prefrontal cortex (PFC) play important role in many physiological functions, such as working memory formation.
The dopamine D4 receptor is highly expressed in PFC. Dysfunction of the dopaminergic system in PFC may lead to the psychophysiology of a variety of disorders, including schizophrenia.
In this article, we will introduce a potent dopamine D4 receptor agonist, PD-168077.
PD-168077, as a selective dopamine D4 receptor agonist, exhibits a Ki of 9 nM.
Additionally, PD-168077 is one of the first agents to be identified as putative selective D4 agonists. It shows >100-fold selectivity over other members of the D2-like receptor family and over their D1-like counterparts.
Furthermore, PD-168077 shows a 20-fold selectivity over α1 and α2, and a 45-fold selectivity over 5-HT1A, Additionally, it exhibits a 460-fold selectivity over 5-HT2A receptors. PD-168077 evidences intrinsic activity at the D4 receptor in terms of quinpirole-like inhibition of forskolin-stimulated cAMP accumulation or stimulation of [3H]thymidine uptake in CHO cells expressing the human D4 receptor. In the PD-168077-treated cell, p-CaMKII exhibits a significantly increased clustering at synaptic sites, as indicated by the enhanced colocalization with PSD-95.
PD-168077 (0.2-25.0 mg/kg) dose-dependently induces locomotion. And this compound takes an unusual and characteristic ”shuffling” form with uncoordinated movements together with yawning, and episodes of myoclonic jerking. And it also reduces grooming, and rearing.
In summary, PD-168077 maleate is a selective dopamine D4 receptor agonist, And it has the potential for schizophrenia research.
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