Nepicastat
(Synonyms: SYN117; RS-25560-197) 目录号 : GC36722
An inhibitor of dopamine β-hydroxylase
Cas No.:173997-05-2
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
Nepicastat is an inhibitor of dopamine β-hydroxylase (DBH; IC50 = 9 nM for the purified human enzyme).1 It is selective for DBH over a panel of 12 enzymes and 13 neurotransmitter receptors (IC50s or Kis = >10 μM). Nepicastat dose-dependently reduces norepinephrine content and increases dopamine content in the mesenteric artery, left ventricle, and cerebral cortex in spontaneously hypertensive rats, as well as in the renal artery, left ventricle, and cerebral cortex in beagle dogs. It attenuates increases in diastolic blood pressure and heart rate induced by preganglionic sympathetic nerve stimulation in pithed spontaneously hypertensive rats when administered orally at doses of 10 and 30 mg/kg.2 Nepicatstat (50 mg/kg) reduces the progressive ratio response for cocaine, but not food or sucrose pellets, in rats.3 It also reduces reinstatement of cocaine-seeking behavior induced by cues, yohimbine , or foot-shock in rats.
1.Stanley, W.C., Li, B., Bonhaus, D.W., et al.Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-β-hydroxylaseBr. J. Pharmacol.121(8)1803-1809(1997) 2.Stanley, W.C., Lee, K., Johnson, L.G., et al.Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine β-hydroxylase inhibitorJ. Cardiovasc. Pharmacol.31(6)963-970(1998) 3.Schroeder, J.P., Epps, S.A., Grice, T.W., et al.The selective dopamine β-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behaviorNeuropsychopharmacology38(6)1032-1038(2013)
| Cas No. | 173997-05-2 | SDF | |
| 别名 | SYN117; RS-25560-197 | ||
| Canonical SMILES | FC1=CC(F)=C2CC[C@@H](CC2=C1)N3C(CN)=CNC3=S | ||
| 分子式 | C14H15F2N3S | 分子量 | 295.35 |
| 溶解度 | DMSO: ≥ 48 mg/mL (162.52 mM) | 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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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.3858 mL | 16.9291 mL | 33.8581 mL |
| 5 mM | 0.6772 mL | 3.3858 mL | 6.7716 mL |
| 10 mM | 0.3386 mL | 1.6929 mL | 3.3858 mL |
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Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder
Front Mol Neurosci 2021 Sep 24;14:745219.PMID:34630037DOI:10.3389/fnmol.2021.745219.
Post-traumatic stress disorder (PTSD) is a common anxiety mental disorder and can be manifested after exposure to a real or perceived life-threatening event. Increased noradrenaline and adrenaline in plasma and urine have been documented in PTSD. Dopamine-β-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and consequently, DBH inhibition reduces catecholamines. Our aim was to evaluate if Nepicastat treatment decreases PTSD signs in an animal model. Wild-type (129x1/SvJ) female mice were submitted to PTSD induction protocol. DBH-inhibitor Nepicastat (30 mg/kg) or vehicle (0.2% HPMC) were administered once daily since day 0 until day 7 or 12. The percentage of freezing was calculated on days 0, 1, 2, and 7, and behavioral tests were performed. Quantification of Nepicastat in plasma and DBH activity in the adrenal gland was evaluated. Catecholamines were quantified by HPLC with electrochemical detection. mRNA expression of Npas4 and Bdnf in hippocampus was evaluated by qPCR.Mice in the PTSD-group and treated with Nepicastat showed a decrease in freezing, and an increase in the time spent and entries in open arms in elevated plus maze test. In mice treated with Nepicastat, adrenal gland DBH activity was decreased, and catecholamines were also decreased in plasma and tissues. On day 7, in mice treated with Nepicastat, there was an increase of Npas4 and Bdnf mRNA expression in the hippocampus.In conclusion, DBH inhibitor Nepicastat has an effect consistent with a decrease in the persistence of traumatic memories and anxiety-like behavior in this PTSD mice model. The disruption of traumatic memories through interference with the formation, consolidation, retrieval, and/or expression processes may be important to decrease PTSD symptoms and signs. The increase in Npas4 and Bdnf mRNA expression in the hippocampus may be important to develop a weaker traumatic contextual memory after Nepicastat treatment.
Effects of Nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland
Clin Exp Hypertens 2020;42(2):118-125.PMID:30821508DOI:10.1080/10641963.2019.1583245.
Background and Objective: Evaluate the activity of dopamine-β-hydroxylase (DβH) as well as the effect of the DβH inhibitor Nepicastat upon enzyme activity and levels of dopamine (DA) and norepinephrine (NE) in the rat left ventricle, kidney, and adrenal glands.Methods: DβH assay consisted of the enzymatic hydroxylation of tyramine into octopamine, and DA and NE tissues levels were quantified by HPLC-ED.Results: Nepicastat (30 mg/kg, p.o.) reduced DβH activity by 93% and 80% in the adrenals at 4 h and 8 h postdrug administration, accompanied by significant reductions in NE and epinephrine tissue levels and an increase in DA levels and of DA/NE tissue ratios, with similar findings for NE, DA and of DA/NE tissue ratios in left ventricle and kidney. DβH activity in the left ventricle and kidney showed a high degree of variability, which does not allow corroboration of the effects of Nepicastat upon catecholamine tissue levels.Conclusion: The assay of DβH activity in heart and kidney lacks the necessary robustness, but DβH activity in the adrenals appears to be an appropriate marker. However, the effect size upon DA/NE tissue ratios (an indirect measure of DβH activity) as induced by Nepicastat was very similar in sympathetically innervated tissues, left ventricle and kidney, and the adrenal medulla.
The dopamine β-hydroxylase inhibitor, Nepicastat, reduces different alcohol-related behaviors in rats
Alcohol Clin Exp Res 2014 Sep;38(9):2345-53.PMID:25257286DOI:10.1111/acer.12520.
Background: Recent experimental data indicate that treatment with the selective dopamine β-hydroxylase inhibitor, Nepicastat, suppressed different reward-related behaviors, including self-administration of chocolate and reinstatement of cocaine and chocolate seeking, in rats. This study was designed to extend to different alcohol-related behaviors the investigation on the "anti-addictive" properties of Nepicastat. Methods: Sardinian alcohol-preferring (sP) rats, selectively bred for excessive alcohol consumption, were exposed to different procedures of alcohol drinking and self-administration. Results: Repeated treatment with Nepicastat (0, 25, 50, and 100 mg/kg, intraperitoneally [i.p.], once daily for 10 consecutive days) produced a stable and dose-related reduction in daily alcohol intake in sP rats exposed to the homecage 2-bottle "alcohol (10% v/v) versus water" choice regimen with unlimited access. Acute treatment with Nepicastat (0, 25, 50, and 100 mg/kg, i.p.) completely suppressed the "alcohol deprivation effect" (i.e., the temporary increase in alcohol intake occurring after a period of abstinence; model of alcohol relapse episodes) in sP rats exposed to the 2-bottle choice regimen. Acute treatment with Nepicastat (0, 25, 50, and 100 mg/kg, i.p.) dose dependently and selectively reduced oral alcohol self-administration in sP rats trained to lever respond for alcohol (15% v/v) on a fixed ratio 4 schedule of reinforcement. Finally, combination of Nepicastat (0, 50, and 100 mg/kg, i.p.) and alcohol (2 g/kg, intragastrically) did not alter spontaneous locomotor activity in sP rats. Conclusions: Together, these data extend to alcohol the capacity of Nepicastat to suppress different behaviors motivated by natural stimuli and drugs of abuse.
Cardiovascular effects of Nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor
J Cardiovasc Pharmacol 1998 Jun;31(6):963-70.PMID:9641484DOI:10.1097/00005344-199806000-00023.
Nepicastat (RS-25560-197) is a novel, selective, and potent inhibitor of dopamine beta-hydroxylase, which modulates catecholamine levels (reduces norepinephrine and elevates dopamine) in cardiovascular tissues. This study was designed to evaluate the cardiovascular effects of Nepicastat. Acute oral administration of Nepicastat (0.3, 1, 3, 10, and 30 mg/kg) produced attenuation of the pressor and positive chronotropic responses to preganglionic sympathetic nerve stimulation (about twofold to sixfold shift in the frequency-response curve) in pithed spontaneously hypertensive rats (SHRs). In inactin-anesthetized SHRs, the antihypertensive effects of Nepicastat (3 mg/kg, i.v.) were accompanied by a significant decrease in renal vascular resistance (38%), a tendency toward an increase in renal blood flow (22%), and no adverse effects on urine output and Na/K excretion. In conscious, unrestrained, telemetry-implanted SHRs, Nepicastat (30 and 100 mg/kg/day for 30 days) produced dose-dependent decreases in mean arterial blood pressure (peak decrease of 20 and 42 mm Hg, respectively) without evoking reflex tachycardia. Long-term, concurrent administration of Nepicastat (30 mg/kg/day, p.o.) and a subthreshold dose of enalapril (1 mg/kg/day, p.o.) produced greater antihypertensive effects than those produced by Nepicastat alone. In normal dogs, Nepicastat (5.0 mg/kg, p.o., b.i.d., for 4.5 days) blunted the positive chronotropic and pressor response to tyramine. These findings suggest that Nepicastat functionally modulates sympathetic drive to cardiovascular tissues and may be of value in the treatment of cardiovascular disorders associated with overactivation of the sympathetic nervous system such as hypertension and congestive heart failure.
The dopamine beta-hydroxylase inhibitor Nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex
Addict Biol 2014 Jul;19(4):612-22.PMID:23289939DOI:10.1111/adb.12026.
The dopamine-beta-hydroxylase inhibitor Nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of Nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking. Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats. Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, Nepicastat markedly potentiated cocaine- and amphetamine-induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by Nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the α2 -adrenoceptor agonist clonidine. It is suggested that Nepicastat, by suppressing noradrenaline synthesis and release, eliminated the α2 -adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine- and amphetamine-induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex.