The Novel Pimavanserin Derivative ST-2300 with Histamine H(3) Receptor Affinity Shows Reduced 5-HT(2A) Binding, but Maintains Antidepressant- and Anxiolytic-like Properties in Mice

The therapy of depression is challenging and still unsatisfactory despite the presence of many antidepressant drugs on the market. Consequently, there is a continuous need to search for new, safer, and more effective antidepressant therapeutics. Previous studies have suggested a potential association of brain histaminergic/serotoninergic signaling and antidepressant- and anxiolytic-like effects. Here, we evaluated the in vivo antidepressant- and anxiolytic-like effects of the newly developed multiple-active ligand ST-2300. ST-2300 was developed from 5-HT(2A/2C) inverse agonist pimavanserin (PIM, ACP-103) and incorporates a histamine H(3) receptor (H(3)R) antagonist pharmacophore. Despite its parent compound, ST-2300 showed only moderate serotonin 5-HT(2A) antagonist/inverse agonist affinity (K(i) value of 1302 nM), but excellent H(3)R affinity (K(i) value of 14 nM). In vivo effects were examined using forced swim test (FST), tail suspension test (TST), and the open field test (OFT) in C57BL/6 mice. Unlike PIM, ST-2300 significantly increased the anxiolytic-like effects in OFT without altering general motor activity. In FST and TST, ST-2300 was able to reduce immobility time similar to fluoxetine (FLX), a recognized antidepressant drug. Importantly, pretreatment with the CNS-penetrant H(3)R agonist (R)-α-methylhistamine reversed the antidepressant-like effects of ST-2300 in FST and TST, but failed to reverse the ST-2300-provided anxiolytic effects in OFT. Present findings reveal critical structural features that are useful in a rational multiple-pharmacological approach to target H(3)R/5-HT(2A)/5-HT(2C).