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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 DSP-1053 (A and B) and paroxetine (C and D) on emotional score in sham-operated and olfactory bulbectomized (OB) rats. Each bar represents the mean ± SEM (n = 9–10 per group). ##P < 0.01 OB group versus sham-operated group (t-test with two-sided significance of 5%). *P < 0.05, **P < 0.01 versus vehicle-treated subgroup in OB group (parametric Dunnett’s multiple comparison test with two-sided significance of 5%).
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fig05: Effects of DSP-1053 (A and B) and paroxetine (C and D) on emotional score in sham-operated and olfactory bulbectomized (OB) rats. Each bar represents the mean ± SEM (n = 9–10 per group). ##P < 0.01 OB group versus sham-operated group (t-test with two-sided significance of 5%). *P < 0.05, **P < 0.01 versus vehicle-treated subgroup in OB group (parametric Dunnett’s multiple comparison test with two-sided significance of 5%).

Mentions: Figure5A and B show the effects of 1- and 2-week administration of DSP-1053 on emotional scores of sham-operated and olfactory bulbectomized animals. Three-way (drug, surgery, and dosing period) ANOVA revealed no main effect for drug × surgery × dosing period, drug × dosing period and surgery × dosing period interaction and a significant main effect for drug × surgery interaction (drug × surgery × dosing period interaction, F(15, 144) = 1.16, P > 0.05; drug × dosing period interaction, F(15, 144) = 0.17, P > 0.05; surgery × dosing period interaction, F(15, 144) = 1.84, P > 0.05; drug × surgery interaction, F(15, 144) = 22.55, P < 0.05). Olfactory bulbectomy significantly increased emotional scores, F(15, 144) = 598.83, P < 0.05. Post hoc test analysis showed that in olfactory bulbectomized animals, DSP-1053 (0.3, 1 and 3 mg/kg) produced a significant decrease in emotional scores, F(3, 76) = 30.58, P < 0.05 and no effect in the sham-operated animals, F(3, 76) = 0.21, P > 0.05. Figure5C and D show the effects of 1- and 2-week administration of paroxetine on emotional scores of sham-operated and olfactory bulbectomized animals. Three-way ANOVA revealed a significant main effect for drug × surgery × dosing period interaction, F(13, 125) = 5.18, P < 0.05. In 1-week administration group, subeffect two-way (drug and surgery) ANOVA revealed that paroxetine did not alter emotional scores compared to the vehicle, F(5, 54) = 0.95, P > 0.05. On the other hand, olfactory bulbectomy significantly increased emotional scores, F(5, 54) = 453.49, P < 0.05, and it did not significantly affect the drug effect – drug × surgery interaction, F(5, 54) = 1.94, P > 0.05. In the 2-week administration group, subeffect two-way (drug and surgery) ANOVA revealed a significant main effect for drug × surgery interaction, F(7, 71) = 4.16, P < 0.05. Post hoc test analysis showed that in olfactory bulbectomized animals, paroxetine (3 and 10 mg/kg) produced a significant decrease in emotional scores, F(3, 35) = 7.38, P < 0.05, and no effect in the sham-operated animals, F(3, 36) = 1.26, 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 DSP-1053 (A and B) and paroxetine (C and D) on emotional score in sham-operated and olfactory bulbectomized (OB) rats. Each bar represents the mean ± SEM (n = 9–10 per group). ##P < 0.01 OB group versus sham-operated group (t-test with two-sided significance of 5%). *P < 0.05, **P < 0.01 versus vehicle-treated subgroup in OB group (parametric Dunnett’s multiple comparison test with two-sided significance of 5%).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Effects of DSP-1053 (A and B) and paroxetine (C and D) on emotional score in sham-operated and olfactory bulbectomized (OB) rats. Each bar represents the mean ± SEM (n = 9–10 per group). ##P < 0.01 OB group versus sham-operated group (t-test with two-sided significance of 5%). *P < 0.05, **P < 0.01 versus vehicle-treated subgroup in OB group (parametric Dunnett’s multiple comparison test with two-sided significance of 5%).
Mentions: Figure5A and B show the effects of 1- and 2-week administration of DSP-1053 on emotional scores of sham-operated and olfactory bulbectomized animals. Three-way (drug, surgery, and dosing period) ANOVA revealed no main effect for drug × surgery × dosing period, drug × dosing period and surgery × dosing period interaction and a significant main effect for drug × surgery interaction (drug × surgery × dosing period interaction, F(15, 144) = 1.16, P > 0.05; drug × dosing period interaction, F(15, 144) = 0.17, P > 0.05; surgery × dosing period interaction, F(15, 144) = 1.84, P > 0.05; drug × surgery interaction, F(15, 144) = 22.55, P < 0.05). Olfactory bulbectomy significantly increased emotional scores, F(15, 144) = 598.83, P < 0.05. Post hoc test analysis showed that in olfactory bulbectomized animals, DSP-1053 (0.3, 1 and 3 mg/kg) produced a significant decrease in emotional scores, F(3, 76) = 30.58, P < 0.05 and no effect in the sham-operated animals, F(3, 76) = 0.21, P > 0.05. Figure5C and D show the effects of 1- and 2-week administration of paroxetine on emotional scores of sham-operated and olfactory bulbectomized animals. Three-way ANOVA revealed a significant main effect for drug × surgery × dosing period interaction, F(13, 125) = 5.18, P < 0.05. In 1-week administration group, subeffect two-way (drug and surgery) ANOVA revealed that paroxetine did not alter emotional scores compared to the vehicle, F(5, 54) = 0.95, P > 0.05. On the other hand, olfactory bulbectomy significantly increased emotional scores, F(5, 54) = 453.49, P < 0.05, and it did not significantly affect the drug effect – drug × surgery interaction, F(5, 54) = 1.94, P > 0.05. In the 2-week administration group, subeffect two-way (drug and surgery) ANOVA revealed a significant main effect for drug × surgery interaction, F(7, 71) = 4.16, P < 0.05. Post hoc test analysis showed that in olfactory bulbectomized animals, paroxetine (3 and 10 mg/kg) produced a significant decrease in emotional scores, F(3, 35) = 7.38, P < 0.05, and no effect in the sham-operated animals, F(3, 36) = 1.26, 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