title: DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats.
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.
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kato
authors.affiliation: Innovative Drug Discovery Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Innovative Drug Discovery Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Baba
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakamichi
authors.affiliation: Innovative Drug Discovery Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Nishimuta
authors.affiliation: Project Management, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yabuuchi
keywords: 5-HT1A receptor; antidepressant; emesis; major depressive disorder; serotonin (5-HT); serotonin reuptake inhibitor; vomiting