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SSR504734

目录号 : GC67871

SSR504734 是一种具有口服活性、选择性和可逆性的 GlyT1 抑制剂 (hGlyT1,rGlyT1,mGlyT1 IC50 分别为 18、15 和 38 nM)。SSR504734 表现出抗精神分裂、抗焦虑和抗抑郁的活性。

SSR504734 Chemical Structure

Cas No.:615571-23-8

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10mg
¥9,450.00
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产品描述

SSR504734 is an orally active, selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively). SSR504734 shows anti-schizophrenia, anti-anxiety and anti-depression activities[1].

SSR504734 (15 nM-86 μM; 10 min) inhibits glycine uptake in human SK-N-MC and rat C6 cells[1].

Cell Viability Assay[1]

Cell Line: Human neuroblastoma (SK-N-MC) and rat astrocytoma (C6) cells
Concentration: 15 nM-86 μM
Incubation Time: 10 min
Result: Showed IC50 values of 18 and 15 nM for human SK-N-MC and rat C6 cells, respectively.

SSR504734 (i.p. and p.o.; 1-100 mg/kg; once) treatment shows good oral bioavailability[1].
SSR504734 (i.p.; 30 mg/kg; once) induces a rapid and significant decrease of specific glycine uptake[1].
SSR504734 (i.p.; 10 mg/kg; once) increases extracellular levels of Glycine in the prefrontal cortex (PFC) of freely moving rats[1].

Animal Model: Male Sprague-Dawley rats[1]
Dosage: 1-100 mg/kg
Administration: Intraperitoneal injection and oral gavage.; 1-100 mg/kg; once
Result: Showed ID50 values of 5.0 and 4.6 mg/kg for i.p. and p.o. treatments, respectively.
Animal Model: Male Sprague-Dawley rats[1]
Dosage: 30 mg/kg
Administration: Intraperitoneal injection; 30 mg/kg; once
Result: Maintained at about 80% inhibition from 1 to 7 h after administration.
Animal Model: Male Sprague-Dawley rats[1]
Dosage: 10 mg/kg
Administration: Intraperitoneal injection; 10 mg/kg; once
Result: Produced a rapid and sustained increase in PFC extracellular levels of glycine.

[1]. Ronan DepoortÈre, et al. Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology. 2005 Nov;30(11):1963-85.

Chemical Properties

Cas No. 615571-23-8 SDF Download SDF
分子式 C20H21Cl2F3N2O 分子量 433.29
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Research Update

SSR504734 enhances basal expression of prepulse inhibition but exacerbates the disruption of prepulse inhibition by apomorphine

Psychopharmacology (Berl) 2013 Nov;230(2):309-17.PMID:23736281DOI:10.1007/s00213-013-3160-3.

Rationale: Inhibition of glycine transporter 1 (GlyT1) elevates extracellular glycine and can thus increase N-methyl-D-aspartate receptor (NMDAR) excitability in the brain. The potent GlyT1 inhibitor, SSR504734, has also been shown to potentiate the behavioral effects of direct and indirect dopamine agonists. Thus, an acute systemic dose of SSR504734 was sufficient to exacerbate the motor-stimulant effect of the dopamine releaser amphetamine in C57BL/6 mice, even though SSR504734 alone exerted no significant effect on motor activity. Objectives: Here, we explore if SSR504734 might modulate dopamine-dependent sensory gating in the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex. Methods: Experiment 1 characterized the effect of SSR504734 (10 and 30 mg/kg i.p.) on PPI expression when administered alone. Experiments 2 and 3 investigated the impact of SSR504734 when administered in conjunction with the dopamine receptor agonist, apomorphine (1 and 2 mg/kg s.c.), which is known to reliably disrupt PPI. Results: When administered alone, acute SSR504734 enhanced PPI only at 30 mg/kg--a dose that has been shown to improve cognitive functions including working memory, which has been linked to enhanced NMDAR function resulting from the elevation of extracellular glycine. However, this effect did not allow SSR504734 to antagonize the PPI-disruptive effect of apomorphine. At the lower dose of 10 mg/kg--that was insufficient to enhance PPI when administered alone--SSR504734 even exacerbated the deleterious effect of apomorphine on PPI. Conclusions: The therapeutic potential of GlyT1 inhibition against distinct behavioral/cognitive deficiency might require different magnitudes of GlyT1 inhibition.

SSR504734, a glycine transporter-1 inhibitor, attenuates acquisition and expression of contextual conditioned fear in rats

Behav Pharmacol 2010 Sep;21(5-6):576-9.PMID:20613495DOI:10.1097/FBP.0b013e32833d419d.

Conditioned stress-induced freezing has been used as an indicator of anxiety in rodents to evaluate the anxiolytic effects of various compounds. However, the role of glycinergic neurotransmission in fear conditioning is not well understood. In this study, we investigated the effects of a selective glycine transporter-1 inhibitor, SSR504734, on contextual fear conditioning. In a fear acquisition experiment, rats were administered SSR504734 (3-30 mg/kg, intraperitoneal) 1 h before fear conditioning (i.e. inescapable footshock). Twenty-four hours after fear conditioning, the rats were placed in the experimental chamber without footshock, and freezing behavior was observed. SSR504734 (30 mg/kg) significantly inhibited contextual conditioned freezing. In a fear expression experiment, rats were administered SSR504734 (3-30 mg/kg, intraperitoneal) 23 h after fear conditioning and were tested 1 h after injection. SSR504734 (30 mg/kg) significantly inhibited contextual conditioned freezing. These findings indicate that SSR504734 attenuates both the acquisition and expression of contextual conditioned fear, and suggest that glycinergic neurotransmission may play an important role in conditioned fear.

Interactions between the glycine transporter 1(GlyT1) inhibitor SSR504734 and psychoactive drugs in mouse motor behaviour

Eur Neuropsychopharmacol 2009 Aug;19(8):571-80.PMID:19282154DOI:10.1016/j.euroneuro.2009.02.004.

The specific glycine transporter 1 (GlyT1) inhibitor, SSR504734, is highly effective in enhancing N-methyl-D-aspartate receptor (NMDAR) function by elevating the availability of the NMDAR co-agonist, glycine, in the vicinity of NMDAR-containing glutamatergic synapses. According to the glutamatergic hypofunction hypothesis of schizophrenia, SSR504734 may therefore possess antipsychotic potential. Here, we evaluated the effects of SSR504734 in response to three psychomimetic drugs: phencyclidine, amphetamine, and apomorphine in male C57BL/6 mice. SSR504734 attenuated phencyclidine-induced (5 mg/kg, i.p.) hyperlocomotion, but potentiated the motor stimulant and motor depressant effects of amphetamine (2.5 mg/kg, i.p.) and apomorphine (0.75 mg/kg, s.c.), respectively. Hence, SSR504734 not only confers resistance to NMDAR blockade, but also enhances the locomotor response to dopaminergic stimulation. The latter finding adds to reports that SSR504734 may modulate dopamine-mediated behaviour by interference with normal glutamate-dopamine interaction. The specificity of this action of SSR504734 will be highly relevant to its potential application as an antipsychotic agent.

Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

EJNMMI Res 2012 Jul 9;2(1):37.PMID:22776065DOI:10.1186/2191-219X-2-37.

Background: Dysfunction of the glycine transporter 1 (GlyT1) has been suggested to be involved in psychiatric disorders such as schizophrenia. GlyT1 inhibitors have therefore been considered to have antipsychotic therapeutic potential. Positron emission tomography (PET) imaging probes for GlyT1 are, consequently, expected to be useful for investigating the mechanism of such disease conditions and for measuring occupancy of GlyT1 inhibitors in vivo. The aim of this study was to assess the potential of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl] 3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET imaging agent for GlyT1. Methods: [11 C]N-methyl-SSR504734 was synthesized by N-[11 C]methylation of SSR504734 via [11 C]CH3OTf. In vitro brain distribution of [11 C]N-methyl-SSR504734 was tested in whole-hemisphere autoradiography (ARG) on human brain slices. Initial PET studies were performed using a cynomolgus monkey at baseline and after pretreatment with 0.1 to 1.5 mg/kg of SSR504734. Then, PET studies using rhesus monkeys were performed with arterial blood sampling at baseline and after pretreatment with 1.5 to 4.5 mg/kg SSR504734. Distribution volumes (VT) were calculated with a two-tissue compartment model, and GlyT1 occupancy by SSR504734 was estimated using a Lassen plot approach. Results: [11 C]N-methyl-SSR504734 was successfully synthesized in moderate radiochemical yield and high specific radioactivity. In the ARG experiments, [11 C]N-methyl-SSR504734 showed specific binding in the white matter and pons. In the initial PET experiments in a cynomolgus monkey, [11 C]N-methyl-SSR504734 showed high brain uptake and consistent distribution with previously reported GlyT1 expression in vivo (thalamus, brainstem > cerebellum > cortical regions). However, the brain uptake increased after pretreatment with SSR504734. Further PET studies in rhesus monkeys showed a similar increase of brain uptake after pretreatment with SSR504734. However, the VT of [11 C]N-methyl-SSR504734 was found to decrease after pretreatment of SSR504734 in a dose-dependent manner. GlyT1 occupancy was calculated to be 45% and 73% at 1.5 and 4.5 mg/kg of SSR504734, respectively. Conclusions: [11 C]N-methyl-SSR504734 is demonstrated to be a promising PET radioligand for GlyT1 in nonhuman primates. The present results warrant further PET studies in human subjects.

The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice

Psychopharmacology (Berl) 2009 Jan;202(1-3):371-84.PMID:18758757DOI:10.1007/s00213-008-1286-5.

Rationale: Inhibition of the glycine transporter 1 (GlyT1) activity increases extra-cellular glycine availability in the CNS. At glutamatergic synapses, increased binding to the glycine-B site located in the N-methyl-D-aspartate receptor (NMDAR) can enhance neurotransmission via NMDARs. Systemic treatment of 2-chloro-N-[(S)-phenyl [(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734), a selective GlyT1 inhibitor, is effective against social recognition impairment induced by neonatal phencyclidine treatment and enhances pre-pulse inhibition in a mouse strain (DBA/2) with intrinsic sensorimotor gating deficiency, suggesting that SSR504734 may be an effective cognitive enhancer. Objective: The objective of the study was to examine if SSR504734 exhibits a promnesic effect on working memory function in wild-type C57BL/6 mice using an automatic continuous alternation task. Materials and methods: Hungry mice were trained to alternate their nose pokes between two food magazines across successive discrete trials in an operant chamber in order to obtain food reward. Correct choice on a given trial thus followed a non-matching or win-shift rule in relation to the preceding trial, with manipulation of the demand on memory retention, by varying the delay between successive trials. Results: Pre-treatment with SSR504734 (30 mg/kg, i.p.) improved choice accuracy when the delay from the previous trial was extended to 12-16 s. Furthermore, a dose-response analysis (3, 10, 30 mg/kg) revealed a clear dose-dependent efficacy of the drug: 3 mg/kg was without effect, whilst 10 mg/kg led to an intermediate enhancement in performance. Conclusion: The present findings represent the first demonstration of the promnesic effects of SSR504734 under normal physiological conditions, lending further support to the suggestion of its potential as a cognitive enhancer.