In Vitro and In Vivo Characterization of PCC0104005, a Novel Modulator of Serotonin-Dopamine Activity, as an Atypical Antipsychotic Drug.

Abstract

PCC0104005 is a novel drug candidate for treating schizophrenia that displays high affinity for serotonin, dopamine, and noradrenaline receptors, including partial agonism at dopamine D2, D3, D4, serotonin 5-HT1A, and 5-HT2A receptors and antagonism at 5-HT2B, 5-HT6, and 5-HT7 receptors. PCC0104005 blocks MK-801-induced hyperactivity in rats, consistent with the reduction in dopamine D2 receptor stimulation and increased dopamine release in the medial prefrontal cortex. PCC0104005 inhibits 5-HTP-induced head twitches in rats, due to its moderate affinity for human 5-HT2A receptors (Ki = 5.1 nM). PCC0104005 significantly reduced the escape latency of rats and improved the MK-801-induced memory impairment. In the object recognition experiment, PCC0104005 significantly improved the recognition disorder induced by MK-801. PCC0104005 did not significantly increase the plasma prolactin level, which is thought to be related to the preferential affinity of PCC0104005 for dopamine D2 receptors compared with 5-HT1A receptors, as well as the relative antagonistic activity toward the D2 receptor. Due to its 5-HT1A agonism, PCC0104005 does not produce catalepsy in mice, a behaviour predictive of the occurrence of extra-pyramidal syndrome (EPS) in humans. PCC0104005 has unique affinities for dopamine receptors and serotonin receptors, which may lead to clinical advantages, as well as fewer adverse reactions.

• Authors: Yanan Xu, Xiaoyin Zhu, Hongbo Wang, Shanyue Sun, Xin Yue, Jingwei Tian
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 6892 (05 02 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29720711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Biomarkers
• Dopamine Agents
• Receptors, Dopamine
• Receptors, Serotonin
• Serotonin Agents
• Dizocilpine Maleate

Topics

• Animals
• Antipsychotic Agents (chemistry, pharmacology)
• Behavior, Animal (drug effects)
• Biomarkers
• Dizocilpine Maleate (pharmacology)
• Dopamine Agents (chemistry, pharmacology)
• Hyperkinesis (drug therapy, metabolism)
• Male
• Maze Learning (drug effects)
• Memory (drug effects)
• Mice
• Rats
• Receptors, Dopamine (metabolism)
• Receptors, Serotonin (metabolism)
• Recognition, Psychology (drug effects)
• Serotonin Agents (chemistry, pharmacology)
• Temperature