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Dual Targeting Ligands—Histamine H 3 Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation

ORCID
0000-0001-8454-4440
Affiliation
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland
Łażewska, Dorota;
Affiliation
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str, 30-688 Kraków, Poland
Siwek, Agata;
ORCID
0000-0002-1466-0742
Affiliation
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland
Olejarz-Maciej, Agnieszka;
Affiliation
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland
Doroz-Płonka, Agata;
ORCID
0000-0003-3452-5748
Affiliation
Department of Pharmacology and Toxicology, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, Poland
Wiktorowska-Owczarek, Anna;
ORCID
0000-0001-9032-1438
Affiliation
Department of Pharmacology and Toxicology, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, Poland
Jóźwiak-Bębenista, Marta;
ORCID
0000-0003-1514-2215
Affiliation
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany
Reiner-Link, David;
Affiliation
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany
Frank, Annika;
Affiliation
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland
Sromek-Trzaskowska, Wioletta;
ORCID
0000-0002-2046-4879
Affiliation
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland
Honkisz-Orzechowska, Ewelina;
ORCID
0000-0001-7812-0887
Affiliation
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland
Królicka, Ewelina;
ORCID
0000-0003-3336-1710
Affiliation
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany
Stark, Holger;
ORCID
0000-0002-0862-8076
Affiliation
Department of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Str., 90-236 Łódź, Poland
Wieczorek, Marek;
Affiliation
Department of Hormone Biochemistry, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, Poland
Wagner, Waldemar;
ORCID
0000-0002-6752-7443
Affiliation
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland
Kieć-Kononowicz, Katarzyna;
ORCID
0000-0002-2225-7312
Affiliation
Department of Hormone Biochemistry, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, Poland
Stasiak, Anna

The clinical symptoms of Parkinson’s disease (PD) appear when dopamine (DA) concentrations in the striatum drops to around 20%. Simultaneous inhibitory effects on histamine H 3 receptor (H 3 R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H 3 R ( h H 3 R) affinity and inhibitory activity to human MAO B (hMAO B). Results showed different activity of the compounds towards the two biological targets. Most compounds had poor affinity for h H 3 R ( K i > 500 nM), but very good inhibitory potency for hMAO B (IC 50 < 50 nM). After further in vitro testing (modality of MAO B inhibition, permeability in PAMPA assay, cytotoxicity on human astrocyte cell lines), the most promising dual-acting ligand, 1-(3-(4-(tert-butyl)phenoxy)propyl)-2-methylpyrrolidine ( 13 : h H 3 R: K i = 25 nM; hMAO B IC 50 = 4 nM) was selected for in vivo evaluation. Studies in rats of compound 13 , in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects for H 3 R (decline in food and a water consumption), decline in MAO B activity (>90%) in rat cerebral cortex (CTX), and an increase in DA content in CTX and striatum. Moreover, compound 13 caused a slight increase in noradrenaline, but a reduction in serotonin concentration in CTX. Thus, compound 13 is a promising dual-active ligand for the potential treatment of PD although further studies are needed to confirm this.

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