AR71, Histamine H 3 Receptor Ligand-In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action)

The future of therapy for neurodegenerative diseases (NDs) relies on new strategies targeting multiple pharmacological pathways. Our research led to obtaining the compound AR71 [(E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one], which has high affinity for human...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-07, Vol.25 (15)
Main Authors: Stasiak, Anna, Honkisz-Orzechowska, Ewelina, Gajda, Zbigniew, Wagner, Waldemar, Popiołek-Barczyk, Katarzyna, Kuder, Kamil J, Latacz, Gniewomir, Juszczak, Michał, Woźniak, Katarzyna, Karcz, Tadeusz, Szczepańska, Katarzyna, Jóźwiak-Bębenista, Marta, Kieć-Kononowicz, Katarzyna, Łażewska, Dorota
Format: Article
Language:English
Subjects:
Analgesics - pharmacology
Animals
Anti-Inflammatory Agents - pharmacology
Cell Line, Tumor
Humans
Ligands
Lipopolysaccharides
Male
Mice
Molecular Docking Simulation
Neuralgia - chemically induced
Neuralgia - drug therapy
Neuralgia - metabolism
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Receptors, Histamine H3 - metabolism
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Summary:The future of therapy for neurodegenerative diseases (NDs) relies on new strategies targeting multiple pharmacological pathways. Our research led to obtaining the compound AR71 [(E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one], which has high affinity for human H R (K = 24 nM) and selectivity towards histamine H and H receptors (K > 2500 nM), and showed anti-inflammatory activity in a model of lipopolysaccharide-induced inflammation in BV-2 cells. The presented tests confirmed its antagonist/inverse agonist activity profile and good metabolic stability while docking studies showed the binding mode to histamine H , H , and H receptors. In in vitro tests, cytotoxicity was evaluated at three cell lines (neuroblastoma, astrocytes, and human peripheral blood mononuclear cells), and a neuroprotective effect was observed in rotenone-induced toxicity. In vivo experiments in a mouse neuropathic pain model demonstrated the highest analgesic effects of AR71 at the dose of 20 mg/kg body weight. Additionally, AR71 showed antiproliferative activity in higher concentrations. These findings suggest the need for further evaluation of AR71's therapeutic potential in treating ND and CNS cancer using animal experimental models.
ISSN:1422-0067