RO5256390
目录号 : GC37548
RO5256390 是微量胺相关受体 1 (TAAR1) 的激动剂，是一种内源性微量胺结合的高度保守的 G 蛋白偶联受体 (GPCR)。RO5256390 可通过药物对中脑皮质系统的作用，减少药物滥用的多种行为效应。RO5256390 是一种单胺，能调节神经传递，可以阻止精神刺激剂引起的亢奋，并产生类似抗精神病药物奥氮平的大脑激活模式，显示出类似抗精神病药物的特性。
Cas No.:1043495-96-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
RO5256390 is an agonist of trace amine-associated receptor 1 (TAAR1), a highly conserved G-protein-coupled receptor (GPCR) bound by endogenous trace amines.RO5256390 can be used to reduce multiple behavioral effects of drugs of abuse through their actions on the mesocorticolimbic system[1].RO5256390 is a modulator of monoaminergic neurotransmission, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties[2].
[1]. Ferragud A, et al. The Trace Amine-Associated Receptor 1 Agonist RO5256390 Blocks Compulsive, Binge-like Eating in Rats. Neuropsychopharmacology. 2017 Jun;42(7):1458-1470. [2]. Revel FG, et al. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry. 2013 May;18(5):543-56.
| Cas No. | 1043495-96-0 | SDF | |
| Canonical SMILES | NC1=N[C@@H](C[C@@H](C2=CC=CC=C2)CC)CO1 | ||
| 分子式 | C13H18N2O | 分子量 | 218.29 |
| 溶解度 | DMSO : 50 mg/mL (229.05 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.5811 mL | 22.9053 mL | 45.8106 mL |
| 5 mM | 0.9162 mL | 4.5811 mL | 9.1621 mL |
| 10 mM | 0.4581 mL | 2.2905 mL | 4.5811 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
The Trace Amine-Associated Receptor 1 Agonist RO5256390 Blocks Compulsive, Binge-like Eating in Rats
Neuropsychopharmacology 2017 Jun;42(7):1458-1470.PMID:27711047DOI:10.1038/npp.2016.233.
Compulsive, binge eating of highly palatable food constitutes a core feature of some forms of obesity and eating disorders, as well as of the recently proposed disorder of food addiction. Trace amine-associated receptor 1 (TAAR1) is a highly conserved G-protein-coupled receptor bound by endogenous trace amines. TAAR1 agonists have been shown to reduce multiple behavioral effects of drugs of abuse through their actions on the mesocorticolimbic system. In this study, we hypothesized that TAAR1 may have a role in compulsive, binge-like eating; we tested this hypothesis by assessing the effects of a TAAR1 agonist, RO5256390, in multiple excessive feeding-related behaviors induced by limiting access to a highly palatable diet in rats. Our results show that RO5256390 blocked binge-like eating in rats responding 1 h per day for a highly palatable sugary diet. Consistent with a palatability-selective effect, drug treatment selectively reduced the rate and regularity of palatable food responding, but it did not affect either baseline intake or food restriction-induced overeating of the standard chow diet. Furthermore, RO5256390 fully blocked compulsive-like eating when the palatable diet was offered in an aversive compartment of a light/dark conflict box, and blocked the conditioned rewarding properties of palatable food, as well as palatable food-seeking behavior in a second-order schedule of reinforcement. Drug treatment had no effect on either anxiety-like or depressive-like behavior, and it did not affect control performance in any of the tests. Importantly, rats exposed to palatable food showed decreased TAAR1 levels in the medial prefrontal cortex (mPFC), and RO5256390 microinfused into the infralimbic, but not prelimbic, subregion of the mPFC-reduced binge-like eating. Altogether, these results provide evidence for TAAR1 agonism as a novel pharmacological treatment for compulsive, binge eating.
Trace Amine Associated Receptor 1 (TAAR1) Modulation of Food Reward
Front Pharmacol 2018 Feb 27;9:129.PMID:29535626DOI:10.3389/fphar.2018.00129.
Eating disorders and some forms of obesity are characterized by addictive-like, compulsive eating behavior which contains numerous similarities with compulsive drug use. Food intake is in part mediated by reward and reinforcement processes that can become dysregulated in these disorders. Additionally, impairments in inhibitory control regulation of reward-related responding can cause or further exacerbate binge and compulsive eating. Dysfunctions in two neurotransmitter systems in the mesocorticolimbic pathway, dopamine and glutamate, are thought to contribute to maladaptive eating behaviors. The trace amine associated receptor 1 (TAAR1) system is a promising therapeutic target for compulsive eating behavior due to the role of TAAR1 in synaptic transmission and in the modulation of dopaminergic and glutamatergic signaling. In support of this notion, the TAAR1 agonist RO5256390 was found to decrease the reinforcing effects of palatable food-cues and to reduce binge-like and compulsive-like eating of palatable food. Additionally, prolonged, intermittent access to palatable food was shown to downregulate TAAR1 in the prefrontal cortex, suggesting a potential role for TAAR1 signaling in inhibitory control processes. Research into the role of TAAR1 in addiction, including TAAR1's ability to modulate psychostimulant reward and reinforcement, bolsters support for TAAR1 agonism as a pharmacological treatment for compulsive eating and other addictive behaviors. This review summarizes the evidence for TAAR1 agonism as a promising therapeutic for compulsive eating behavior as well as the hypothesized mechanism responsible for these effects.
Effects of acute and chronic administration of trace amine-associated receptor 1 (TAAR1) ligands on in vivo excitability of central monoamine-secreting neurons in rats
Mol Psychiatry 2022 Dec;27(12):4861-4868.PMID:36045279DOI:10.1038/s41380-022-01739-9.
Trace amine-associated receptor 1 (TAAR1) has been recently identified as a target for the future antidepressant, antipsychotic, and anti-addiction drugs. Full (e.g. RO5256390) and partial (e.g. RO5263397) TAAR1 agonists showed antidepressant-, antipsychotic- and anti-addiction-like behavioral effects in rodents and primates. Acute RO5256390 suppressed, and RO5263397 stimulated serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopamine neurons of the ventral tegmental area (VTA) in brain slices, suggesting that the behavioral effects of TAAR1 ligands involve 5-HT and dopamine. For more comprehensive testing of this hypothesis, we examined acute and chronic effects of RO5256390 and RO5263397 on monoamine neurons in in vivo conditions. Excitability of 5-HT neurons of the DRN, noradrenaline neurons of the locus coeruleus (LC), and dopamine neurons of the VTA was assessed using single-unit electrophysiology in anesthetized rats. For acute experiments, RO5256390 and RO5263397 were administered intravenously; neuronal excitability after RO5256390 and RO5263397 administration was compared to the basal activity of the same neuron. For chronic experiments, RO5256390 was administered orally for fourteen days prior to electrophysiological assessments. The neuronal excitability in RO5256390-treated rats was compared to vehicle-treated controls. We found that acute RO5256390 inhibited 5-HT and dopamine neurons. This effect of RO5256390 was reversed by the subsequent and prevented by the earlier administration of RO5263397. Acute RO5256390 and RO5263397 did not alter the excitability of LC noradrenaline neurons in a statistically significant way. Chronic RO5256390 increased excitability of 5-HT neurons of the DRN and dopamine neurons of the VTA. In conclusion, the putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons.
Central and peripheral methylamine-induced hypophagia is mediated via nitric oxide and TAAR1 in neonatal layer-type chicken
Neurosci Lett 2020 Nov 20;739:135408.PMID:33027685DOI:10.1016/j.neulet.2020.135408.
The aim of the current study was to determine effects of intracerebroventricular (ICV) and intraperitoneal (i.p.) administration of Methylamine (MET) and possible interactions with nitric oxide (NO) and TAAR1 pathways in 24-h fasted (FD24) and ad libitum layer-type chicken. In experiment 1, FD24 chicken ICV injected with MET (15, 30, 45, 60 and 75 μg). In experiment 2, ICV injection of MET (15, 30, 45, 60 and 75 μg) was injected in the ad libitum birds. Experiments 3-4 were similar to experiments 1-2, except chicken i.p. injected with MET (15, 30, 45, 60 and 75 mg/kg). In experiment 5, FD24 birds ICV injected with l-NAME (NO synthesis inhibitor, 100 nmol), MET (75 μg) and co-injection of l-NAME + MET. Experiment 6 was similar to experiment 5, except, ad libitum birds received injections. In experiment 7, FD24 chicken i.p. injected with l-NAME (100 mg/kg), MET (75 mg/kg) and co-injection of l-NAME + MET. In experiment 8, FD24 birds ICV injected with RO5256390 (selective TAAR1 agonist, 10, 20 and 40 μg). In experiment 9, ad libitum birds ICV injected with RO5256390 (10, 20 and 40 μg). In experiment 10, FD24 birds ICV injected with RO5256390 (10 μg), MET (75 μg) and their co-injection. Experiment 11 was similar to experiment 10, except, ad libitum birds received ICV injections. In experiment 12, FD24 chicken i.p. injected with RO5256390 (2.5, 5 and 10 mg/kg). In experiment 13, FD24 chicken i.p. injected with RO5256390 (2.5 mg/kg), MET (75 mg/kg) and RO5256390 + MET. Then cumulative food intake was determined until 120 min after injection. According to the results, ICV injection of MET decreased food intake in FD24 and ad libitum chicken (P < 0.05). MET (i.p.) diminished food consumption in fasted (P < 0.05) but not in ad libitum chicken (P> 0.05). Co-injection of the l-NAME + MET significantly decreased MET-induced hypophagia in FD24 and ad libitum chicken (P < 0.05). MET-induced hypophagia (i.p.) weakened by l-NAME in FD24 chicken (P < 0.05). RO5256390 decreased food intake in FD24 and ad libitum chicken (P < 0.05). Co-injection of RO5256390 + MET increased MET-induced hypophagia in FD24 and ad libitum chicken (P < 0.05). RO5256390 decreased food intake in FD24 chicken (P < 0.05). Co-injection of the RO5256390 + MET amplified MET-induced hypophagia in FD24 chicken (P < 0.05). Based on the findings, MET-induced hypophagia is mediated via NO and TAAR1 pathways on food intake in layer chicken.
Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics
Biol Psychiatry 2017 Nov 1;82(9):623-633.PMID:27919403DOI:10.1016/j.biopsych.2016.10.012.
Background: Narcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy. Methods: In the first experiment, male homozygous B6-Taar1tm1(NLSLacZ)Blt (Taar1 knockout) and wild-type mice were surgically implanted to record electroencephalogram, electromyogram, locomotor activity, and body temperature, and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, locomotor activity, body temperature, and cataplexy were assessed in two mouse narcolepsy models. Results: RO5256390 profoundly reduced rapid eye movement sleep in wild-type mice; these effects were eliminated in Taar1 knockout mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed nonrapid eye movement sleep. Both compounds reduced body temperature in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the narcolepsy models. The therapeutic benefit was mediated through a reduction in number of cataplexy episodes and time spent in cataplexy. Conclusions: These results suggest TAAR1 agonism as a new therapeutic pathway for treatment of this orphan disease. The common underlying mechanism may be the suppression of rapid eye movement sleep.