Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters
Monoamine transporters, including dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively), are important therapeutic targets due to their essential roles in the brain. To overcome the slow action of selective monoamine reuptake inhibitors, dual- or triple-acting inhib...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/10/2846 |
| _version_ | 1797574592313688064 |
|---|---|
| author | Hyomin Ahn Kichul Park Dongyoung Kim Sung-Gil Chi Kee-Hyun Choi Seo-Jung Han Chiman Song |
| author_facet | Hyomin Ahn Kichul Park Dongyoung Kim Sung-Gil Chi Kee-Hyun Choi Seo-Jung Han Chiman Song |
| author_sort | Hyomin Ahn |
| collection | DOAJ |
| description | Monoamine transporters, including dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively), are important therapeutic targets due to their essential roles in the brain. To overcome the slow action of selective monoamine reuptake inhibitors, dual- or triple-acting inhibitors have been developed. Here, to examine whether combination treatments of selective reuptake inhibitors have synergistic effects, the pharmacological properties of DAT, NET, and SERT were investigated using the selective inhibitors of each transporter, which are vanoxerine, nisoxetine, and fluoxetine, respectively. Potencies were determined via fluorescence-based substrate uptake assays in the absence and presence of other inhibitors to test the multi-drug effects on individual transporters, resulting in antagonistic effects on DAT. In detail, fluoxetine resulted in a 1.6-fold increased IC<sub>50</sub> value of vanoxerine for DAT, and nisoxetine produced a more drastic increase in the IC<sub>50</sub> value by six folds. Furthermore, the effects of different inhibitors, specifically monovalent ions, were tested on DAT inhibition by vanoxerine. Interestingly, these ions also reduced vanoxerine potency in a similar manner. The homology models of DAT suggested a potential secondary inhibitor binding site that affects inhibition in an allosteric manner. These findings imply that the use of combination therapy with monoamine reuptake inhibitors should be approached cautiously, as antagonistic effects may occur. |
| first_indexed | 2024-03-10T21:24:39Z |
| format | Article |
| id | doaj.art-994692cf78634bf1a827887f379e9027 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T21:24:39Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-994692cf78634bf1a827887f379e90272023-11-19T15:47:56ZengMDPI AGBiomedicines2227-90592023-10-011110284610.3390/biomedicines11102846Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine TransportersHyomin Ahn0Kichul Park1Dongyoung Kim2Sung-Gil Chi3Kee-Hyun Choi4Seo-Jung Han5Chiman Song6Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of KoreaOZIWORX, R&D Laboratory, 130-2, Donghwagongdan-ro, Gangwon-do, Wonju-si 26365, Republic of KoreaOZIWORX, R&D Laboratory, 130-2, Donghwagongdan-ro, Gangwon-do, Wonju-si 26365, Republic of KoreaDepartment of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of KoreaChemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of KoreaChemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of KoreaChemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of KoreaMonoamine transporters, including dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively), are important therapeutic targets due to their essential roles in the brain. To overcome the slow action of selective monoamine reuptake inhibitors, dual- or triple-acting inhibitors have been developed. Here, to examine whether combination treatments of selective reuptake inhibitors have synergistic effects, the pharmacological properties of DAT, NET, and SERT were investigated using the selective inhibitors of each transporter, which are vanoxerine, nisoxetine, and fluoxetine, respectively. Potencies were determined via fluorescence-based substrate uptake assays in the absence and presence of other inhibitors to test the multi-drug effects on individual transporters, resulting in antagonistic effects on DAT. In detail, fluoxetine resulted in a 1.6-fold increased IC<sub>50</sub> value of vanoxerine for DAT, and nisoxetine produced a more drastic increase in the IC<sub>50</sub> value by six folds. Furthermore, the effects of different inhibitors, specifically monovalent ions, were tested on DAT inhibition by vanoxerine. Interestingly, these ions also reduced vanoxerine potency in a similar manner. The homology models of DAT suggested a potential secondary inhibitor binding site that affects inhibition in an allosteric manner. These findings imply that the use of combination therapy with monoamine reuptake inhibitors should be approached cautiously, as antagonistic effects may occur.https://www.mdpi.com/2227-9059/11/10/2846monoamine transporterdopamine transporterantagonistic effectvanoxerinenisoxetinefluoxetine |
| spellingShingle | Hyomin Ahn Kichul Park Dongyoung Kim Sung-Gil Chi Kee-Hyun Choi Seo-Jung Han Chiman Song Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters Biomedicines monoamine transporter dopamine transporter antagonistic effect vanoxerine nisoxetine fluoxetine |
| title | Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters |
| title_full | Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters |
| title_fullStr | Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters |
| title_full_unstemmed | Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters |
| title_short | Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters |
| title_sort | implications for combination therapy of selective monoamine reuptake inhibitors on dopamine transporters |
| topic | monoamine transporter dopamine transporter antagonistic effect vanoxerine nisoxetine fluoxetine |
| url | https://www.mdpi.com/2227-9059/11/10/2846 |
| work_keys_str_mv | AT hyominahn implicationsforcombinationtherapyofselectivemonoaminereuptakeinhibitorsondopaminetransporters AT kichulpark implicationsforcombinationtherapyofselectivemonoaminereuptakeinhibitorsondopaminetransporters AT dongyoungkim implicationsforcombinationtherapyofselectivemonoaminereuptakeinhibitorsondopaminetransporters AT sunggilchi implicationsforcombinationtherapyofselectivemonoaminereuptakeinhibitorsondopaminetransporters AT keehyunchoi implicationsforcombinationtherapyofselectivemonoaminereuptakeinhibitorsondopaminetransporters AT seojunghan implicationsforcombinationtherapyofselectivemonoaminereuptakeinhibitorsondopaminetransporters AT chimansong implicationsforcombinationtherapyofselectivemonoaminereuptakeinhibitorsondopaminetransporters |