![(R)-Nepicastat HCl [RS-25560-198 HCl]](/upload/0201/CgAGS12aCm6AB2_7AABKJJYDSXY189.png)
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Purity: ≥98%
(R)-Nepicastat HCl (R-SYN117; R-SYN-117; R-RS-25560-198 HCl), the R-enantiomer of Nepicastat HCl (RS-25560-197; SYN117; SYN-117; RS25560197), is a selective inhibitor with IC50 of 25.1 nM and 18.3 nM for bovine and human dopamine-β-hydroxylases (enzymes catalyzing the transformation of dopamine to norepinephrine) with the potential to treat congestive heart failure.
| Targets |
Dopamine-β-hydroxylase (bovine IC50 = 25.1 ± 0.6 nM; human IC50 = 18.3 ± 0.6 nM) [1]
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| ln Vitro |
In vitro activity: (R)-Nepicastat produces concentration-dependent inhibition of bovine and human dopamine-β-hydroxylase activity in vitro. In vitro enzyme inhibition: (R)-Nepicastat HCl [RS-25560-198 HCl] produced concentration-dependent inhibition of bovine dopamine-β-hydroxylase with an IC50 of 25.1 ± 0.6 nM and human dopamine-β-hydroxylase with an IC50 of 18.3 ± 0.6 nM, showing approximately 2-3 fold lower potency compared to the S-enantiomer (nepicastat) [1]. |
| ln Vivo |
(R)-Nepicastat (30 mg/kg, p.o.) reduces noradrenaline content, dopamine content and dopamine/noradrenaline ratio in mesenteric artery and left ventricle of spontaneously hypertensive rats (SHRs).
In vivo catecholamine modulation in spontaneously hypertensive rats (SHRs): When administered orally at 30 mg/kg three consecutive times 12 h apart, (R)-Nepicastat HCl [RS-25560-198 HCl] significantly altered tissue noradrenaline and dopamine content. In the mesenteric artery, it reduced noradrenaline to 8.91 ± 0.9 μg/g (control 10.4 ± 1.03) and increased dopamine to 0.67 ± 0.09 μg/g (control 0.25 ± 0.02), resulting in dopamine/noradrenaline ratio of 0.08 ± 0.01 (control 0.03 ± 0.00). In the left ventricle, noradrenaline was 1.16 ± 0.08 μg/g (control 1.30 ± 0.06), dopamine 0.07 ± 0.00 μg/g (control 0.02 ± 0.00), ratio 0.06 ± 0.01 (control 0.02 ± 0.00). In the cerebral cortex, noradrenaline was 0.88 ± 0.02 μg/g (control 0.76 ± 0.03), dopamine 0.18 ± 0.00 μg/g (control 0.14 ± 0.01), ratio 0.20 ± 0.01 (control 0.19 ± 0.01). Compared to nepicastat, RS-25560-198 produced significantly smaller changes in noradrenaline and dopamine content in the mesenteric artery and left ventricle [1]. |
| Enzyme Assay |
Bovine and human dopamine-β-hydroxylase activity was assayed by measuring the conversion of tyramine to octopamine. Bovine adrenal enzyme was obtained commercially, while human enzyme was purified from neuroblastoma cell line SK-NSH culture medium. The assay was performed at pH 5.2 and 32°C in a medium containing sodium acetate, fumarate, CuSO4, catalase, tyramine, and ascorbate. Enzyme was added to the reaction mixture, followed by substrate mixture containing catalase, tyramine, and ascorbate to initiate the reaction. Samples were incubated with or without test compound at 37°C for 30-40 min. The reaction was quenched with a stop solution containing EDTA and 3-hydroxytyramine (internal standard). Octopamine was analyzed by reverse-phase HPLC with UV detection at 280 nm. The HPLC run used a LiChroCART RP-18 column with isocratic elution using acetic acid, 1-heptane sulphonic acid, tetrabutyl ammonium phosphate, and methanol at a flow rate of 1 ml/min. Remaining activity percentage was calculated based on controls, corrected with internal standards, and fitted to a non-linear four-parameter concentration-response curve [1].
Additionally, the affinity of (R)-Nepicastat HCl [RS-25560-198 HCl] for twelve other enzymes (including tyrosine hydroxylase, acetyl CoA synthetase, acyl CoA-cholesterol acyl transferase, Ca2+/calmodulin-protein kinase II, cyclo-oxygenase-I, HMG-CoA reductase, neutral endopeptidase, nitric oxide synthase, phosphodiesterase III, phospholipase A2, and protein kinase C) and thirteen neurotransmitter receptors (α1A, α1B, α2A, α2B, β1, β2 adrenoceptors, M1 muscarinic, D1, D2 dopamine, μ opioid, 5-HT1A, 5-HT2A, 5-HT2C serotonin receptors) was evaluated using established radioligand binding or enzymatic assays. The compound had negligible affinity (IC50 or Ki > 10 μM) for all these targets [1]. |
| Animal Protocol |
Dissolved in distilled water; 30 mg/kg; p.o. Animal Models Spontaneously hypertensive rats (SHRs).
Spontaneously hypertensive rats (SHRs): Male SHRs (15-16 weeks old) were randomly assigned to receive either vehicle (distilled water) or (R)-Nepicastat HCl [RS-25560-198 HCl] at 30 mg/kg (free base equivalent) orally via gavage needle, three consecutive times, twelve hours apart. Six hours after the third dose, rats were anaesthetized with halothane, decapitated, and tissues (cerebral cortex, mesenteric artery, left ventricle) were rapidly harvested, weighed, placed in ice-cold perchloric acid, frozen in liquid nitrogen, and stored at -70°C until analysis. Noradrenaline and dopamine concentrations were quantified by HPLC with electrochemical detection after tissue homogenization and centrifugation [1]. |
| References |
Br J Pharmacol.1997 Aug;121(8):1803-9.
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| Additional Infomation |
(R)-Nepicastat HCl [RS-25560-198 HCl] is the R-enantiomer of nepicastat (RS-25560-197). It is a less potent inhibitor of dopamine-β-hydroxylase compared to the S-enantiomer, exhibiting stereospecificity in its inhibitory activity. The compound was tested alongside nepicastat in comparative studies of catecholamine modulation [1].
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| Molecular Formula |
C14H15F2N3S.HCL
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| Molecular Weight |
331.81
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| Exact Mass |
331.072
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| CAS # |
195881-94-8
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| Related CAS # |
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| PubChem CID |
54536287
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
4.514
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
20
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| Complexity |
429
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| Defined Atom Stereocenter Count |
1
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| SMILES |
Cl.NCC1=CNC(=S)N1[C@@H]1CCC2=C(C=C(C=C2C1)F)F
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| InChi Key |
YZZVIKDAOTXDEB-SNVBAGLBSA-N
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| InChi Code |
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)/t10-/m1/s1
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| Chemical Name |
4-(aminomethyl)-3-[(2R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-1H-imidazole-2-thione
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0138 mL | 15.0689 mL | 30.1377 mL | |
| 5 mM | 0.6028 mL | 3.0138 mL | 6.0275 mL | |
| 10 mM | 0.3014 mL | 1.5069 mL | 3.0138 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Figure 2Effects of nepicastat on tissue noradrenaline (NA) and dopamine (DA) content in the mesenteric artery (a), left ventricle (b) and cerebral cortex (c) of SHRs.Br J Pharmacol.1997 Aug;121(8):1803-9. |
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COA
Effects of nepicastat on tissue dopamine/noradrenaline ratio in the mesenteric artery, left ventricle and cerebral cortex of SHRs.