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DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats.

Kato T, Matsumoto Y, Yamamoto M, Matsumoto K, Baba S, Nakamichi K, Matsuda H, Nishimuta H, Yabuuchi K - Pharmacol Res Perspect (2015)

Bottom Line: In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time.In olfactory bulbectomy model, 1- and 2-week administration of DSP-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 DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes.

View Article: PubMed Central - PubMed

Affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.

ABSTRACT
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 DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the K i values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg(-1), dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-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 DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.

No MeSH data available.


Related in: MedlinePlus

Effects of 7-day treatment with DSP-1053 or paroxetine on the number of vomiting episodes in Suncus murinus. Each column represents the mean ± SEM of the number of emetic episodes. The number above each column represents the incidence of vomiting as the number of animals that vomited/the number of animals tested. *P < 0.05, **P < 0.01, significantly different from the number of vomiting episodes observed in Day 1 using Dunnett’s multiple comparison test.
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fig08: Effects of 7-day treatment with DSP-1053 or paroxetine on the number of vomiting episodes in Suncus murinus. Each column represents the mean ± SEM of the number of emetic episodes. The number above each column represents the incidence of vomiting as the number of animals that vomited/the number of animals tested. *P < 0.05, **P < 0.01, significantly different from the number of vomiting episodes observed in Day 1 using Dunnett’s multiple comparison test.

Mentions: In experiment 1, DSP-1053 at the dose of 10, 30, or 60 mg kg−1 induced emesis in 0, 1, or 3 of 6 animals, respectively, whereas, as shown in Table4, paroxetine at 10, 30, or 60 mg kg−1 induced emesis in 0, 2, or 6 of 6 animals, respectively (Mine et al. 2013). In experiment 2, both DSP-1053 (60 mg kg−1) and paroxetine (60 mg kg−1) induced emesis in 9 and 12 of 19 animals, respectively. Figure8 shows the incidence of vomiting and the number of vomiting episodes during a 60-min period in each day of a 7-day consecutive administration of DSP-1053 or paroxetine. A significant reduction in the number of vomiting episodes was observed from Day 2 in DSP-1053-treated group, F(6, 56) = 5.60, P < 0.05. On the other hand, repeated administration of paroxetine did not have significant effect on the number of vomiting episodes throughout the 7-day administration period, F(6, 77) = 1.64, P > 0.05.


DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats.

Kato T, Matsumoto Y, Yamamoto M, Matsumoto K, Baba S, Nakamichi K, Matsuda H, Nishimuta H, Yabuuchi K - Pharmacol Res Perspect (2015)

Effects of 7-day treatment with DSP-1053 or paroxetine on the number of vomiting episodes in Suncus murinus. Each column represents the mean ± SEM of the number of emetic episodes. The number above each column represents the incidence of vomiting as the number of animals that vomited/the number of animals tested. *P < 0.05, **P < 0.01, significantly different from the number of vomiting episodes observed in Day 1 using Dunnett’s multiple comparison test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492758&req=5

fig08: Effects of 7-day treatment with DSP-1053 or paroxetine on the number of vomiting episodes in Suncus murinus. Each column represents the mean ± SEM of the number of emetic episodes. The number above each column represents the incidence of vomiting as the number of animals that vomited/the number of animals tested. *P < 0.05, **P < 0.01, significantly different from the number of vomiting episodes observed in Day 1 using Dunnett’s multiple comparison test.
Mentions: In experiment 1, DSP-1053 at the dose of 10, 30, or 60 mg kg−1 induced emesis in 0, 1, or 3 of 6 animals, respectively, whereas, as shown in Table4, paroxetine at 10, 30, or 60 mg kg−1 induced emesis in 0, 2, or 6 of 6 animals, respectively (Mine et al. 2013). In experiment 2, both DSP-1053 (60 mg kg−1) and paroxetine (60 mg kg−1) induced emesis in 9 and 12 of 19 animals, respectively. Figure8 shows the incidence of vomiting and the number of vomiting episodes during a 60-min period in each day of a 7-day consecutive administration of DSP-1053 or paroxetine. A significant reduction in the number of vomiting episodes was observed from Day 2 in DSP-1053-treated group, F(6, 56) = 5.60, P < 0.05. On the other hand, repeated administration of paroxetine did not have significant effect on the number of vomiting episodes throughout the 7-day administration period, F(6, 77) = 1.64, P > 0.05.

Bottom Line: In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time.In olfactory bulbectomy model, 1- and 2-week administration of DSP-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 DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes.

View Article: PubMed Central - PubMed

Affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.

ABSTRACT
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 DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the K i values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg(-1), dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-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 DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.

No MeSH data available.


Related in: MedlinePlus