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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

Chemical structure of DSP-1053.
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fig01: Chemical structure of DSP-1053.

Mentions: DSP-1053 (6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one benzenesulfonate) (Fig.1) and paroxetine hydrochloride (paroxetine) were synthesized in our laboratories. The rout of synthesis of DSP-1053 has been described previously (Nishida et al. 2012). Clomipramine hydrochloride (clomipramine), serotonin hydrochloride (5-HT), dopamine hydrochloride (dopamine), imipramine hydrochloride (imipramine), WAY-100635, pindolol, and R-(+)-8-hydroxy-DPAT (8-OH-DPAT) were purchased from Sigma Aldrich Japan (Tokyo, Japan). All radioligands were purchased from Perkin Elmer Japan (Kanagawa, Japan). For oral (p.o.) administration in rodent models, DSP-1053 and paroxetine were dissolved in 0.5% methylcellulose. In the S. murinus model, DSP-1053 and paroxetine were dissolved in 40% polyethylene glycol. Dosing volume was determined based on each animal body weight measured in the morning of each administration day (5 mL kg−1). Cell membranes expressing human serotonin transporter and 5-HT1A receptor were purchased from Perkin Elmer Japan. Chinese hamster ovary cells expressing human serotonin transporter used for [3H]5-HT uptake assay were established in our Pharmacology Research Laboratories at Sumitomo Dainippon Pharma Co., Ltd.


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)

Chemical structure of DSP-1053.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Chemical structure of DSP-1053.
Mentions: DSP-1053 (6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one benzenesulfonate) (Fig.1) and paroxetine hydrochloride (paroxetine) were synthesized in our laboratories. The rout of synthesis of DSP-1053 has been described previously (Nishida et al. 2012). Clomipramine hydrochloride (clomipramine), serotonin hydrochloride (5-HT), dopamine hydrochloride (dopamine), imipramine hydrochloride (imipramine), WAY-100635, pindolol, and R-(+)-8-hydroxy-DPAT (8-OH-DPAT) were purchased from Sigma Aldrich Japan (Tokyo, Japan). All radioligands were purchased from Perkin Elmer Japan (Kanagawa, Japan). For oral (p.o.) administration in rodent models, DSP-1053 and paroxetine were dissolved in 0.5% methylcellulose. In the S. murinus model, DSP-1053 and paroxetine were dissolved in 40% polyethylene glycol. Dosing volume was determined based on each animal body weight measured in the morning of each administration day (5 mL kg−1). Cell membranes expressing human serotonin transporter and 5-HT1A receptor were purchased from Perkin Elmer Japan. Chinese hamster ovary cells expressing human serotonin transporter used for [3H]5-HT uptake assay were established in our Pharmacology Research Laboratories at Sumitomo Dainippon Pharma Co., Ltd.

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