Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation
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<sub>3</sub> receptor (H<sub>3</sub>R) and MAO B can increase DA levels in the brain. A series of comp...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/10/2187 |
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| author | Dorota Łażewska Agata Siwek Agnieszka Olejarz-Maciej Agata Doroz-Płonka Anna Wiktorowska-Owczarek Marta Jóźwiak-Bębenista David Reiner-Link Annika Frank Wioletta Sromek-Trzaskowska Ewelina Honkisz-Orzechowska Ewelina Królicka Holger Stark Marek Wieczorek Waldemar Wagner Katarzyna Kieć-Kononowicz Anna Stasiak |
| author_facet | Dorota Łażewska Agata Siwek Agnieszka Olejarz-Maciej Agata Doroz-Płonka Anna Wiktorowska-Owczarek Marta Jóźwiak-Bębenista David Reiner-Link Annika Frank Wioletta Sromek-Trzaskowska Ewelina Honkisz-Orzechowska Ewelina Królicka Holger Stark Marek Wieczorek Waldemar Wagner Katarzyna Kieć-Kononowicz Anna Stasiak |
| author_sort | Dorota Łażewska |
| collection | DOAJ |
| description | 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<sub>3</sub> receptor (H<sub>3</sub>R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H<sub>3</sub>R (<i>h</i>H<sub>3</sub>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 <i>h</i>H<sub>3</sub>R (<i>K<sub>i</sub></i> > 500 nM), but very good inhibitory potency for hMAO B (IC<sub>50</sub> < 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 (<b>13</b>: <i>h</i>H<sub>3</sub>R: <i>K<sub>i</sub></i> = 25 nM; hMAO B IC<sub>50</sub> = 4 nM) was selected for in vivo evaluation. Studies in rats of compound <b>13</b>, in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects for H<sub>3</sub>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 <b>13</b> caused a slight increase in noradrenaline, but a reduction in serotonin concentration in CTX. Thus, compound <b>13</b> is a promising dual-active ligand for the potential treatment of PD although further studies are needed to confirm this. |
| first_indexed | 2024-03-09T19:34:51Z |
| format | Article |
| id | doaj.art-9d182e4dcb5d4290bc05ad6a476c576a |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T19:34:51Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-9d182e4dcb5d4290bc05ad6a476c576a2023-11-24T01:57:49ZengMDPI AGPharmaceutics1999-49232022-10-011410218710.3390/pharmaceutics14102187Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo EvaluationDorota Łażewska0Agata Siwek1Agnieszka Olejarz-Maciej2Agata Doroz-Płonka3Anna Wiktorowska-Owczarek4Marta Jóźwiak-Bębenista5David Reiner-Link6Annika Frank7Wioletta Sromek-Trzaskowska8Ewelina Honkisz-Orzechowska9Ewelina Królicka10Holger Stark11Marek Wieczorek12Waldemar Wagner13Katarzyna Kieć-Kononowicz14Anna Stasiak15Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, PolandDepartment of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str, 30-688 Kraków, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, PolandDepartment of Pharmacology and Toxicology, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, PolandDepartment of Pharmacology and Toxicology, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, PolandInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, GermanyDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, PolandInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, GermanyDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Str., 90-236 Łódź, PolandDepartment of Hormone Biochemistry, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, PolandDepartment of Hormone Biochemistry, Medical University of Lodz, Żeligowskiego 7/9 Str., 90-752 Łódź, PolandThe 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<sub>3</sub> receptor (H<sub>3</sub>R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H<sub>3</sub>R (<i>h</i>H<sub>3</sub>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 <i>h</i>H<sub>3</sub>R (<i>K<sub>i</sub></i> > 500 nM), but very good inhibitory potency for hMAO B (IC<sub>50</sub> < 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 (<b>13</b>: <i>h</i>H<sub>3</sub>R: <i>K<sub>i</sub></i> = 25 nM; hMAO B IC<sub>50</sub> = 4 nM) was selected for in vivo evaluation. Studies in rats of compound <b>13</b>, in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects for H<sub>3</sub>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 <b>13</b> caused a slight increase in noradrenaline, but a reduction in serotonin concentration in CTX. Thus, compound <b>13</b> is a promising dual-active ligand for the potential treatment of PD although further studies are needed to confirm this.https://www.mdpi.com/1999-4923/14/10/2187histamine H<sub>3</sub> receptorhistamine H<sub>3</sub> receptor ligandmonoamine oxidase B (MAO B)MAO B inhibitordual-target ligandspitolisant |
| spellingShingle | Dorota Łażewska Agata Siwek Agnieszka Olejarz-Maciej Agata Doroz-Płonka Anna Wiktorowska-Owczarek Marta Jóźwiak-Bębenista David Reiner-Link Annika Frank Wioletta Sromek-Trzaskowska Ewelina Honkisz-Orzechowska Ewelina Królicka Holger Stark Marek Wieczorek Waldemar Wagner Katarzyna Kieć-Kononowicz Anna Stasiak Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation Pharmaceutics histamine H<sub>3</sub> receptor histamine H<sub>3</sub> receptor ligand monoamine oxidase B (MAO B) MAO B inhibitor dual-target ligands pitolisant |
| title | Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation |
| title_full | Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation |
| title_fullStr | Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation |
| title_full_unstemmed | Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation |
| title_short | Dual Targeting Ligands—Histamine H<sub>3</sub> Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation |
| title_sort | dual targeting ligands histamine h sub 3 sub receptor ligands with monoamine oxidase b inhibitory activity in vitro and in vivo evaluation |
| topic | histamine H<sub>3</sub> receptor histamine H<sub>3</sub> receptor ligand monoamine oxidase B (MAO B) MAO B inhibitor dual-target ligands pitolisant |
| url | https://www.mdpi.com/1999-4923/14/10/2187 |
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