Ahn Hyomin Kichul Park Dongyoung Kim Sung-Gil Chi Kee-Hyun Choi Han, Seojung Song, Chiman 2024-01-12T06:33:31Z 2024-01-12T06:33:31Z 2023-10-21 2023-10 2227-9059 https://pubs.kist.re.kr/handle/201004/79801 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 IC50 value of vanoxerine for DAT, and nisoxetine produced a more drastic increase in the IC50 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. English MDPI AG Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters Article 10.3390/biomedicines11102846 1 Biomedicines, v.11, no.10 Biomedicines 11 10 Y scie scopus 001094006100001 Biochemistry & Molecular Biology Medicine, Research & Experimental Pharmacology & Pharmacy Biochemistry & Molecular Biology Research & Experimental Medicine Pharmacology & Pharmacy Article BACTERIAL HOMOLOG UPTAKE BLOCKERS RAT-BRAIN BINDING SEROTONIN CHOLINE COCAINE CATIONS NA+ antagonistic effect vanoxerine nisoxetine fluoxetine monoamine transporter dopamine transporter