464899-27-2

Upstream product

• 767-00-0 4-cyanophenol 
• 5472-49-1 1-(3-chloropropyl)piperidine hydrochloride 

Downstream Products

• 1258290-16-2 5-hydroxy-2-((4-(3-(piperidin-1-yl)propoxy)benzylamino)methyl)-4H-pyran-4-one 
• 1258290-13-9 N-benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine 
• 1258290-14-0 N,N-dibenzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine 

Relevant academic research and scientific papers

The Novel Pimavanserin Derivative ST-2300 with Histamine H3 Receptor Affinity Shows Reduced 5-HT2A 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 anxio-lytic-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-HT2A/2C inverse agonist pimavanserin (PIM, ACP-103) and incorporates a histamine H3 receptor (H3R) antagonist pharmacophore. Despite its parent compound, ST-2300 showed only moderate serotonin 5-HT2A antagonist/inverse agonist affinity (Ki value of 1302 nM), but excellent H3R affinity (Ki 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 H3R agonist (R)-α-methylhistamine reversed the antidepres-sant-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 multi-ple-pharmacological approach to target H3R/5-HT2A/5-HT2C.

First metal-containing histamine H3 receptor ligands

Iron-containing ligands targeting the human histamine H3 receptor (hH3R) were prepared. The compounds contain ferrocene sandwich complexes coupled via different linkers to a basic hH3R antagonist/inverse agonist pharmacophore. In a click chemistry approach, a triazole was successfully inserted as a new linking element. Two ferrocenylmethylamines and a ferrocenyltriazole were the most affine hH 3R ligands within this series, showing receptor binding in the nano- and subnanomolar concentration range.

Kojic acid derivatives as histamine H3 receptor ligands

The histamine H3 receptor (H3R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H3R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H3R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of γ-pyranones with respect to the different moieties of the H3R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H3R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H3R ligands with a modified profile of action.