Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant Properties
In an attempt to find new dual acting histamine H<sub>3</sub> receptor (H<sub>3</sub>R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H<sub>3</sub> receptor (hH<...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/26/8/2300 |
| _version_ | 1827695030112878592 |
|---|---|
| author | Kamil J. Kuder Magdalena Kotańska Katarzyna Szczepańska Kamil Mika David Reiner-Link Holger Stark Katarzyna Kieć-Kononowicz |
| author_facet | Kamil J. Kuder Magdalena Kotańska Katarzyna Szczepańska Kamil Mika David Reiner-Link Holger Stark Katarzyna Kieć-Kononowicz |
| author_sort | Kamil J. Kuder |
| collection | DOAJ |
| description | In an attempt to find new dual acting histamine H<sub>3</sub> receptor (H<sub>3</sub>R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H<sub>3</sub> receptor (hH<sub>3</sub>R) ligand KSK63. As a result, 15 obtained compounds show moderate hH<sub>3</sub>R affinity, the best being the compound <b>17</b> (hH<sub>3</sub>R <i>K</i><sub>i</sub> = 518 nM). Docking to the histamine H<sub>3</sub>R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound <b>16</b> (hH<sub>3</sub>R <i>K</i><sub>i</sub> = 592 nM) showed the strongest antioxidant properties at the concentration of 10<sup>−4</sup> mol/L. It significantly reduced the amount of free radicals presenting 50–60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH<sub>3</sub>R affinity, <b>16</b> (QD13) constitutes a starting point for the search of potential dual acting H<sub>3</sub>R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress. |
| first_indexed | 2024-03-10T12:17:54Z |
| format | Article |
| id | doaj.art-f6dc552355194124acf7001217757fb2 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T12:17:54Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f6dc552355194124acf7001217757fb22023-11-21T15:46:01ZengMDPI AGMolecules1420-30492021-04-01268230010.3390/molecules26082300Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant PropertiesKamil J. Kuder0Magdalena Kotańska1Katarzyna Szczepańska2Kamil Mika3David Reiner-Link4Holger Stark5Katarzyna Kieć-Kononowicz6Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-699 Kraków, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-699 Kraków, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-699 Kraków, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-699 Kraków, PolandInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Duesseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Duesseldorf, GermanyDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-699 Kraków, PolandIn an attempt to find new dual acting histamine H<sub>3</sub> receptor (H<sub>3</sub>R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H<sub>3</sub> receptor (hH<sub>3</sub>R) ligand KSK63. As a result, 15 obtained compounds show moderate hH<sub>3</sub>R affinity, the best being the compound <b>17</b> (hH<sub>3</sub>R <i>K</i><sub>i</sub> = 518 nM). Docking to the histamine H<sub>3</sub>R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound <b>16</b> (hH<sub>3</sub>R <i>K</i><sub>i</sub> = 592 nM) showed the strongest antioxidant properties at the concentration of 10<sup>−4</sup> mol/L. It significantly reduced the amount of free radicals presenting 50–60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH<sub>3</sub>R affinity, <b>16</b> (QD13) constitutes a starting point for the search of potential dual acting H<sub>3</sub>R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.https://www.mdpi.com/1420-3049/26/8/2300histamine H<sub>3</sub> receptorhistamine H<sub>3</sub> receptor ligandspiperazine derivativesmolecular modelingantioxidative agents |
| spellingShingle | Kamil J. Kuder Magdalena Kotańska Katarzyna Szczepańska Kamil Mika David Reiner-Link Holger Stark Katarzyna Kieć-Kononowicz Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant Properties Molecules histamine H<sub>3</sub> receptor histamine H<sub>3</sub> receptor ligands piperazine derivatives molecular modeling antioxidative agents |
| title | Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant Properties |
| title_full | Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant Properties |
| title_fullStr | Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant Properties |
| title_full_unstemmed | Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant Properties |
| title_short | Discovery of Potential, Dual-Active Histamine H<sub>3</sub> Receptor Ligands with Combined Antioxidant Properties |
| title_sort | discovery of potential dual active histamine h sub 3 sub receptor ligands with combined antioxidant properties |
| topic | histamine H<sub>3</sub> receptor histamine H<sub>3</sub> receptor ligands piperazine derivatives molecular modeling antioxidative agents |
| url | https://www.mdpi.com/1420-3049/26/8/2300 |
| work_keys_str_mv | AT kamiljkuder discoveryofpotentialdualactivehistaminehsub3subreceptorligandswithcombinedantioxidantproperties AT magdalenakotanska discoveryofpotentialdualactivehistaminehsub3subreceptorligandswithcombinedantioxidantproperties AT katarzynaszczepanska discoveryofpotentialdualactivehistaminehsub3subreceptorligandswithcombinedantioxidantproperties AT kamilmika discoveryofpotentialdualactivehistaminehsub3subreceptorligandswithcombinedantioxidantproperties AT davidreinerlink discoveryofpotentialdualactivehistaminehsub3subreceptorligandswithcombinedantioxidantproperties AT holgerstark discoveryofpotentialdualactivehistaminehsub3subreceptorligandswithcombinedantioxidantproperties AT katarzynakieckononowicz discoveryofpotentialdualactivehistaminehsub3subreceptorligandswithcombinedantioxidantproperties |