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 .