Nepicastat

Inhibitor of dopamine-β-hydroxylase,potent and selective CAS# 173997-05-2

Nepicastat

Catalog No. BCC1795----Order now to get a substantial discount!

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Chemical structure

Nepicastat

3D structure

Chemical Properties of Nepicastat

Cas No. 173997-05-2 SDF Download SDF
PubChem ID 6367078 Appearance Powder
Formula C14H15F2N3S M.Wt 295.35
Type of Compound N/A Storage Desiccate at -20°C
Synonyms SYN117; RS-25560-197
Solubility DMSO : ≥ 48 mg/mL (162.52 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 5-(aminomethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazol-1-ium-2-thione
SMILES C1CC2=C(C=C(C=C2CC1[NH+]3C(=CNC3=S)CN)F)F
Standard InChIKey YZZVIKDAOTXDEB-UHFFFAOYSA-O
Standard InChI InChI=1S/C14H15F2N3S/c15-9-3-8-4-10(1-2-12(8)13(16)5-9)19-11(6-17)7-18-14(19)20/h3,5,7,10H,1-2,4,6,17H2,(H,18,20)/p+1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Nepicastat

DescriptionNepicastat is a selective inhibitor of dopamine β-hydroxylase (DBH) with IC50 value of 9 nM.
TargetsDBH    
IC509 nM     

Nepicastat Dilution Calculator

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Nepicastat Molarity Calculator

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Preparing Stock Solutions of Nepicastat

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.3858 mL 16.9291 mL 33.8581 mL 67.7163 mL 84.6453 mL
5 mM 0.6772 mL 3.3858 mL 6.7716 mL 13.5433 mL 16.9291 mL
10 mM 0.3386 mL 1.6929 mL 3.3858 mL 6.7716 mL 8.4645 mL
50 mM 0.0677 mL 0.3386 mL 0.6772 mL 1.3543 mL 1.6929 mL
100 mM 0.0339 mL 0.1693 mL 0.3386 mL 0.6772 mL 0.8465 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Nepicastat

Nepicastat is a potent and selective inhibitor of dopamine-β-hydroxylase with IC50 values of 8.5 and 9.0 nM in bovine and human, respectively [1].

Dopamine-β-hydroxylase is an enzyme involved in the synthesis of small-molecule membrane-bound neurotransmitters. Dopamine-β-hydroxylase catalyses the synthesis of noradrenaline [1].

Nepicastat is a potent and selective dopamine-β-hydroxylase inhibitor. (R)-Nepicastat exhibited 2-3 fold less potent than nepicastat [1].

In beagle dogs and spontaneously hypertensive rats, nepicastat reduced noradrenaline in a dose-dependent way and increased dopamine and dopamine/noradrenaline ratio in cerebral cortex, left ventricle and the artery. In beagle dogs, nepicastat (2 mg/kg) significantly reduced noradrenaline by 52% and increased dopamine by 646% and dopamine/noradrenaline ratio in plasma [1]. In pithed spontaneously hypertensive rats, nepicastat inhibited the pressor and positive chronotropic due to preganglionic sympathetic nerve stimulation. In spontaneously hypertensive rats, nepicastat (3 mg/kg) exhibited antihypertensive effects and reduced renal vascular resistance by 38% [2]. In rats, nepicastat significantly increased extracellular dopamine accumulation induced by cocaine and amphetamine in the medial prefrontal cortex [3].

References:
[1].  Stanley WC, Li B, Bonhaus DW, et al. Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase. Br J Pharmacol, 1997, 121(8): 1803-1809.
[2].  Stanley WC, Lee K, Johnson LG, et al. Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor. J Cardiovasc Pharmacol, 1998, 31(6): 963-970.
[3].  Devoto P, Flore G, Saba P, et al. The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex. Addict Biol, 2014, 19(4): 612-622.

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References on Nepicastat

Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-beta-hydroxylase: comparison with nepicastat.[Pubmed:25641750]

Eur J Pharmacol. 2015 Mar 15;751:50-8.

The interaction of etamicastat, a novel peripherally acting dopamine-beta-hydroxylase (DBH) inhibitor, with the enzyme was studied using a classical kinetic approach and the pharmacodynamics effect of the compound upon administration to rats was also evaluated. SK-N-SH cell homogenates convert tyramine into octopamine with a Km value of 9 mM, and a Vmax of 1747 nmol/mg protein/h. The K(m) value for ascorbate was 3 mM. The inhibition of DBH by etamicastat and Nepicastat, a known centrally acting DBH inhibitor, with IC50 values of 107 and 40 nM, respectively, was fully reversed by dilution. Non-linear fitting of the velocities, determined at various concentrations of substrate (tyramine) and co-substrate (ascorbic acid), and of etamicastat and Nepicastat, indicated that the inhibition of DBH by both compounds follows a mixed-model inhibition mechanism, approaching competitive behavior with regards to the substrate tyramine, with K(i) values of 34 and 11 nM, respectively. Relatively to ascorbate, both compounds followed a mixed-model inhibition mechanism, approaching uncompetitive behavior. Oral administration of both compounds (at 30 mg/kg) inhibited adrenal DBH activity over time and significantly decreased noradrenaline levels in the heart. Nepicastat also decreased noradrenaline levels in the parietal cortex, but not etamicastat. Both compounds significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats. In conclusion, etamicastat and Nepicastat behave as multisubstrate DBH inhibitors, binding reversibly and preferentially to the reduced form of the enzyme, and simultaneously at the substrate and oxygen binding sites. Etamicastat, in contrast to Nepicastat, offers the advantage of peripheral selectivity without central effects.

The dopamine beta-hydroxylase inhibitor, nepicastat, reduces different alcohol-related behaviors in rats.[Pubmed:25257286]

Alcohol Clin Exp Res. 2014 Sep;38(9):2345-53.

BACKGROUND: Recent experimental data indicate that treatment with the selective dopamine beta-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.

Evaluation of the dopamine beta-hydroxylase (DbetaH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.[Pubmed:25602710]

Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jun 3;59:40-48.

In the present study, we tested the hypothesis that the potent and selective dopamine-beta-hydroxylase (DbetaH) inhibitor Nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral Nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that Nepicastat was well-tolerated and there were no differences in adverse events observed after Nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by Nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to Nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of Nepicastat or 160mg of Nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of Nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that Nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.

Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat.[Pubmed:25915108]

Xenobiotica. 2015;45(9):828-39.

1. This study explores the impact of permeability and P-glycoprotein (P-gp) efflux, upon brain exposure to etamicastat, a new dopamine-beta-hydroxylase (DBH) inhibitor and consequently brain levels of catecholamines. 2. Brain exposure to etamicastat (10 mg/kg), following intravenous administration to mice, was residual and upon oral administration of the same dose no compound was detected, concurring with the absence of effects upon brain catecholamines. The intravenous co-administration of elacridar (1.0 mg/kg), a known P-gp/BCRP dual modulator, significantly increased brain etamicastat exposure, but the levels attained were very low when compared to those of Nepicastat, a centrally active DBH inhibitor. 3. In vitro permeability studies from apical-to-basal direction conducted in Caco-2 cells and MDCK-II cells showed that etamicastat apparent permeability was 1.2 x 10(-5) and 1.1 x 10(-6 )cm/s, respectively, 5- and 50-fold lower as compared to Nepicastat. The secretory efflux ratio in MDCK-II cells overexpressing human P-gp showed an efflux ratio greater than 2, for both compounds, which was significantly decreased by elacridar. Despite its lower bioavailability and higher clearance, as compared to Nepicastat, etamicastat showed preferential distribution to peripheral tissues and high plasma free fraction (15.5%), which may explain its effects upon peripheral DBH and catecholamine levels. 4. Though P-gp-mediated efflux may contribute to the limited brain penetration of etamicastat, the low permeability along with the pharmacokinetic properties of etamicastat may be perceived as the main contributors for its peripheral selectivity, which is advantageous for a cardiovascular drug candidate.

Description

Nepicastat (SYN117) is a selective, potent, and orally active inhibitor of dopamine-beta-hydroxylase. Nepicastat (SYN117) produces concentration-dependent inhibition of bovine (IC50=8.5 nM) and human (IC50=9 nM) dopamine-beta-hydroxylase. Nepicastat (SYN117) can cross the blood-brain barrier (BBB).

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