Nepicastat HCl
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MedKoo CAT#: 510304

CAS#: 170151-24-3 (HCl)

Description: Nepicastat, also known as SYN117 and RS-25560-197, is an inhibitor of dopamine beta-hydroxylase, an enzyme that catalyzes the conversion of dopamine to norepinephrine. It has been studied as a possible treatment for congestive heart failure, and appears to be well tolerated. As of 2012, clinical trials to assess nepicastat as a treatment for post-traumatic stress disorder (PTSD) and cocaine dependence have been completed. In Phase 2 study treatment with nepicastat was not effective in relieving PTSD-associated symptoms when compared to placebo.


Chemical Structure

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Nepicastat HCl
CAS# 170151-24-3 (HCl)

Theoretical Analysis

MedKoo Cat#: 510304
Name: Nepicastat HCl
CAS#: 170151-24-3 (HCl)
Chemical Formula: C14H15F2N3S
Exact Mass:
Molecular Weight: 295.35
Elemental Analysis: C, 56.93; H, 5.12; F, 12.86; N, 14.23; S, 10.86

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 850.0 Ready to ship
500.0mg USD 1850.0 Ready to ship
1.0g USD 3150.0 Ready to ship
2.0g USD 5650.0 Ready to ship
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Related CAS #: 170151-24-3 (HCl)   173997-05-2 (free base)   195881-94-8 (HCl   R isomer)  

Synonym: SYN117; SYN-117; SYN 117; RS25560197; RS25560-197; RS-25560-197; RS 25560-197; Nepicastat; Nepicastat HCl

IUPAC/Chemical Name: (S)-5-(aminomethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-imidazole-2(3H)-thione hydrochloride

InChi Key: DIPDUAJWNBEVOY-PPHPATTJSA-N

InChi Code: InChI=1S/C14H15F2N3S.ClH/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);1H/t10-;/m0./s1

SMILES Code: S=C1NC=C(CN)N1[C@@H]2CC3=C(C(F)=CC(F)=C3)CC2.[H]Cl

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Nepicastat (SYN-117) HCl is a potent and selective inhibitor of both bovine and human dopamine-β-hydroxylase with IC50 of 8.5 nM and 9 nM, with negligible affinity for twelve other enzymes and thirteen neurotransmitter receptors.
In vitro activity: Under the optimized conditions, nepicastat inhibited SK-N-SH DBH enzyme (Fig. 4) with IC50 values of 40 (36; 44) nM. The inhibition produced by 300 nM nepicastat was fully reversed by a two-step centrifugation and dilution procedure (data not shown). The modality of DBH inhibition by nepicastat was evaluated in relation to two of the enzyme substrates, tyramine and ascorbic acid. The velocities determined at increasing concentrations of tyramine in the presence of 10, 30 and 100 nM of nepicastat are shown in Fig. 6A and the ones determined at increasing concentrations of ascorbic acid in the presence of 10 and 30 nM nepicastat are represented in Fig. 6B. Non-linear regression analysis was performed as above. The kinetic parameters Ki and constant α derived from these curves are shown in Table 1. Concerning the substrate ascorbic acid, nepicastat inhibits DBH with a Ki value of 0.1 (0.0; 0.5) µM. Reference: Eur J Pharmacol. 2015 Mar 15;751:50-8. https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(15)00067-9
In vivo activity: 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. Reference: Clin Exp Hypertens. 2020;42(2):118-125. https://www.tandfonline.com/doi/full/10.1080/10641963.2019.1583245

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 6.0 20.3

Preparing Stock Solutions

The following data is based on the product molecular weight 295.35 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Bicker J, Alves G, Fortuna A, Soares-da-Silva P, Falcão A. In vitro assessment of the interactions of dopamine β-hydroxylase inhibitors with human P-glycoprotein and Breast Cancer Resistance Protein. Eur J Pharm Sci. 2018 May 30;117:35-40. doi: 10.1016/j.ejps.2018.02.006. Epub 2018 Feb 8. PMID: 29428540. 2. Bonifácio MJ, Sousa F, Neves M, Palma N, Igreja B, Pires NM, Wright LC, Soares-da-Silva P. Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: comparison with nepicastat. Eur J Pharmacol. 2015 Mar 15;751:50-8. doi: 10.1016/j.ejphar.2015.01.034. Epub 2015 Jan 29. PMID: 25641750.
In vivo protocol: 1. Catelas DN, Serrão MP, Soares-Da-Silva P. 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. doi: 10.1080/10641963.2019.1583245. Epub 2019 Mar 1. PMID: 30821508. 2. Stanley WC, Lee K, Johnson LG, Whiting RL, Eglen RM, Hegde SS. Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor. J Cardiovasc Pharmacol. 1998 Jun;31(6):963-70. doi: 10.1097/00005344-199806000-00023. PMID: 9641484.

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1: Devoto P, Fattore L, Antinori S, Saba P, Frau R, Fratta W, Gessa GL. Elevated dopamine in the medial prefrontal cortex suppresses cocaine seeking via D1 receptor overstimulation. Addict Biol. 2014 Aug 19. doi: 10.1111/adb.12178. [Epub ahead of print] PubMed PMID: 25135633.

2: Cooper DA, Kimmel HL, Manvich DF, Schmidt KT, Weinshenker D, Howell LL. Effects of pharmacologic dopamine β-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther. 2014 Jul;350(1):144-52. doi: 10.1124/jpet.113.212357. Epub 2014 May 9. PubMed PMID: 24817036; PubMed Central PMCID: PMC4056266.

3: Manvich DF, DePoy LM, Weinshenker D. Dopamine β-hydroxylase inhibitors enhance the discriminative stimulus effects of cocaine in rats. J Pharmacol Exp Ther. 2013 Dec;347(3):564-73. doi: 10.1124/jpet.113.207746. Epub 2013 Sep 25. PubMed PMID: 24068832; PubMed Central PMCID: PMC3836309.

4: Zaru A, Maccioni P, Colombo G, Gessa GL. The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats. Br J Nutr. 2013 Oct;110(8):1524-33. doi: 10.1017/S0007114513000743. Epub 2013 Apr 8. PubMed PMID: 23561307.

5: Schroeder JP, Epps SA, Grice TW, Weinshenker D. The selective dopamine β-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behavior. Neuropsychopharmacology. 2013 May;38(6):1032-8. doi: 10.1038/npp.2012.267. Epub 2013 Jan 3. PubMed PMID: 23303068; PubMed Central PMCID: PMC3629392.

6: Devoto P, Flore G, Saba P, Bini V, Gessa GL. 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. doi: 10.1111/adb.12026. Epub 2013 Jan 7. PubMed PMID: 23289939.

7: Gaval-Cruz M, Liles LC, Iuvone PM, Weinshenker D. Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice. PLoS One. 2012;7(11):e50583. doi: 10.1371/journal.pone.0050583. Epub 2012 Nov 27. PubMed PMID: 23209785; PubMed Central PMCID: PMC3507785.

8: Kapoor A, Shandilya M, Kundu S. Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms. PLoS One. 2011;6(10):e26509. doi: 10.1371/journal.pone.0026509. Epub 2011 Oct 20. PubMed PMID: 22028891; PubMed Central PMCID: PMC3197665.

9: Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D. Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase. Neuropsychopharmacology. 2010 Nov;35(12):2440-9. doi: 10.1038/npp.2010.127. Epub 2010 Aug 25. PubMed PMID: 20736996; PubMed Central PMCID: PMC2956132.

10: Gaval-Cruz M, Schroeder JP, Liles LC, Javors MA, Weinshenker D. Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures. Pharmacol Biochem Behav. 2008 Jun;89(4):556-62. doi: 10.1016/j.pbb.2008.02.009. Epub 2008 Feb 12. PubMed PMID: 18329701; PubMed Central PMCID: PMC2386143.



Additional Information

  Related CAS#
170151-24-3 ( Nepicastat HCl);
173997-05-2 ( Nepicastat free base).