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

PCC0104005 is a novel drug candidate for treating schizophrenia that displays high affinity for serotonin, dopamine, and noradrenaline receptors, including partial agonism at dopamine D(2), D(3), D(4), serotonin 5-HT(1A), and 5-HT(2A) receptors and antagonism at 5-HT(2B), 5-HT(6), and 5-HT(7) receptors. PCC0104005 blocks MK-801-induced hyperactivity in rats, consistent with the reduction in dopamine D(2) 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-HT(2A) 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 D(2) receptors compared with 5-HT(1A) receptors, as well as the relative antagonistic activity toward the D(2) receptor. Due to its 5-HT(1A) 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.