DSP‐1053, a novel serotonin reuptake inhibitor with 5‐HT_1Apartial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats

<jats:title>Abstract</jats:title><jats:p>Enhancement of serotonergic neurotransmission has been the main stream of treatment for patients with depression. However, delayed therapeutic onset and undesirable side effects are major drawbacks for conventional serotonin reuptake inhibitors. Here, we show that<jats:styled-content style="fixed-case">DSP</jats:styled-content>‐1053, a novel serotonin reuptake inhibitor with 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>1A</jats:sub>partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models.<jats:styled-content style="fixed-case">DSP</jats:styled-content>‐1053 bound human serotonin transporter and 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>1A</jats:sub>receptor with the<jats:italic>K</jats:italic><jats:sub>i</jats:sub>values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an<jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub>value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>1A</jats:sub>receptors of 70.0 ± 6.3%. In rat microdialysis,<jats:styled-content style="fixed-case">DSP</jats:styled-content>‐1053, given once at 3 and 10 mg kg<jats:sup>−1</jats:sup>, dose‐dependently increased extracellular 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content>levels. In the rat forced swimming test, 2‐week administration of<jats:styled-content style="fixed-case">DSR</jats:styled-content>‐1053 (1 mg kg<jats:sup>−1</jats:sup>) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg<jats:sup>−1</jats:sup>) required 3‐week administration to reduce rats immobility time. In olfactory bulbectomy model, 1‐ and 2‐week administration of<jats:styled-content style="fixed-case">DSP</jats:styled-content>‐1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects. Although single administration of<jats:styled-content style="fixed-case">DSP</jats:styled-content>‐1053‐induced emesis and vomiting in the rat and<jats:italic>Suncus murinus</jats:italic>, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>1A</jats:sub>receptors in both the efficacy and tolerability of<jats:styled-content style="fixed-case">DSP</jats:styled-content>‐1053 as a new therapeutic option for the treatment of depression.</jats:p>