Nepicastat

Nepicastat
Names
Preferred IUPAC name
5-(Aminomethyl)-1-[(2S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-1,3-dihydro-2H-imidazole-2-thione
Other names
SYN-117
Identifiers
CAS Number
  • 173997-05-2 checkY
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:139334
ChemSpider
  • 7971947 checkY
IUPHAR/BPS
  • 6630
MeSH Nepicastat
PubChem CID
  • 9796181
UNII
  • VPG12K4540 checkY
CompTox Dashboard (EPA)
  • DTXSID80169740 Edit this at Wikidata
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)/t10-/m0/s1 checkY
    Key: YZZVIKDAOTXDEB-JTQLQIEISA-N checkY
  • InChI=1/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-/m0/s1
    Key: YZZVIKDAOTXDEB-JTQLQIEIBJ
  • Fc1cc3c(c(F)c1)CC[C@H](N2/C(=C\NC2=S)CN)C3
Properties
Chemical formula
 C14H15F2N3S
Molar mass 295.35 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Chemical compound

Nepicastat (INN, codenamed SYN117, RS-25560-197) is an inhibitor of dopamine beta-hydroxylase (DBH), an enzyme that catalyzes the conversion of dopamine to norepinephrine.[1]

It has been studied as a possible treatment for congestive heart failure, and appears to be well tolerated as such.[2] As of 2012, clinical trials to assess nepicastat as a treatment for post-traumatic stress disorder (PTSD) and cocaine dependence have been completed.[3][4] In Phase 2 study treatment with nepicastat was not effective in relieving PTSD-associated symptoms when compared to placebo. The study was funded by the U.S. Department of Defense.[5]

Mice lacking epinephrine exhibit reduced contextual memory after fear conditioning .[6] In addition, in PTSD epinephrine enhances traumatic contextual memory.[7] Studies indicate that nepicastat effectively reduces norepinephrine in both peripheral and central tissues in rats[8] [9] and dogs.[10] Nepicastat also upregulates the transcription Npas4 and Bdnf genes in the mice hippocampus potentially contributing to neuronal regulation and the attenuation of traumatic contextual memories [11][12] No DBH inhibitor has received marketing approval due to poor DBH selectivity, low potency and side effects, however DBH gene silencing may be an alternative for patients with heightened sympathetic activity.[13] Some studies, however have shown that nepicastat is well-tolerated in healthy adults and no significant differences in adverse events were observed.[14] Given that nepicastat treatment has been proven to be effective in reducing signs in an PTSD mouse model with increased catecholamine levels, [15] it could be a promising treatment option for humans with PTSD characterized by increased catecholamine plasma levels.[16]

References

  1. ^ Stanley WC, Li B, Bonhaus DW, Johnson LG, Lee K, Porter S, et al. (August 1997). "Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase". British Journal of Pharmacology. 121 (8): 1803–1809. doi:10.1038/sj.bjp.0701315. PMC 1564872. PMID 9283721.
  2. ^ Hegde SS, Friday KF (December 1998). "Dopamine-beta-hydroxylase inhibition: a novel sympatho-modulatory approach for the treatment of congestive heart failure". Current Pharmaceutical Design. 4 (6): 469–479. doi:10.2174/138161280406221011113124. PMID 10197057.
  3. ^ "Pharmacogenetic Clinical Trial of Nepicastat for Post Traumatic Stress Disorder (PTSD)". ClinicalTrials.gov. U.S. National Institutes of Health. June 4, 2008. Retrieved on February 1, 2012.
  4. ^ "Study of Safety and Potential Efficacy of SYN117 in Cocaine Dependent Volunteers". ClinicalTrials.gov. U.S. National Institutes of Health. August 15, 2008. Retrieved on February 1, 2012.
  5. ^ Biotie reports top-line data from clinical study with nepicastat (SYN117) in post-traumatic stress disorder BIOTIE THERAPIES CORP. STOCK EXCHANGE RELEASE 27 December 2012.
  6. ^ Alves E, Lukoyanov N, Serrão P, Moura D, Moreira-Rodrigues M (June 2016). "Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors". Psychopharmacology. 233 (11): 2099–2108. doi:10.1007/s00213-016-4254-5. PMID 26935825.
  7. ^ Martinho R, Oliveira A, Correia G, Marques M, Seixas R, Serrão P, et al. (2020-10-26). "Epinephrine May Contribute to the Persistence of Traumatic Memories in a Post-traumatic Stress Disorder Animal Model". Frontiers in Molecular Neuroscience. 13: 588802. doi:10.3389/fnmol.2020.588802. PMC 7649334. PMID 33192300.
  8. ^ Bonifácio MJ, Sousa F, Neves M, Palma N, Igreja B, Pires NM, et al. (March 2015). "Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: comparison with nepicastat". European Journal of Pharmacology. 751: 50–58. doi:10.1016/j.ejphar.2015.01.034. PMID 25641750.
  9. ^ Loureiro AI, Bonifácio MJ, Fernandes-Lopes C, Pires N, Igreja B, Wright LC, et al. (2015-09-02). "Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 45 (9): 828–839. doi:10.3109/00498254.2015.1018985. PMID 25915108.
  10. ^ Stanley WC, Li B, Bonhaus DW, Johnson LG, Lee K, Porter S, et al. (August 1997). "Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase". British Journal of Pharmacology. 121 (8): 1803–1809. doi:10.1038/sj.bjp.0701315. PMC 1564872. PMID 9283721.
  11. ^ Martinho R, Correia G, Seixas R, Oliveira A, Silva S, Serrão P, et al. (2021-09-24). "Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder". Frontiers in Molecular Neuroscience. 14: 745219. doi:10.3389/fnmol.2021.745219. PMC 8498196. PMID 34630037.
  12. ^ Moreira-Rodrigues M, Grubisha MJ (2022-12-08). "Editorial: Molecular mechanisms of neuropsychiatric diseases". Frontiers in Molecular Neuroscience. 15: 1102296. doi:10.3389/fnmol.2022.1102296. PMC 9773978. PMID 36568276.
  13. ^ Azevedo M, Martinho R, Oliveira A, Correia-de-Sá P, Moreira-Rodrigues M (2024-01-08). "Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder". Frontiers in Molecular Neuroscience. 16: 1332348. doi:10.3389/fnmol.2023.1332348. PMC 10800988. PMID 38260808.
  14. ^ De La Garza R, Bubar MJ, Carbone CL, Moeller FG, Newton TF, Anastasio NC, et al. (June 2015). "Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 59: 40–48. doi:10.1016/j.pnpbp.2015.01.009. PMC 4777897. PMID 25602710.
  15. ^ Martinho R, Correia G, Seixas R, Oliveira A, Silva S, Serrão P, et al. (2021-09-24). "Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder". Frontiers in Molecular Neuroscience. 14: 745219. doi:10.3389/fnmol.2021.745219. PMC 8498196. PMID 34630037.
  16. ^ Azevedo M, Martinho R, Oliveira A, Correia-de-Sá P, Moreira-Rodrigues M (2024-01-08). "Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder". Frontiers in Molecular Neuroscience. 16: 1332348. doi:10.3389/fnmol.2023.1332348. PMC 10800988. PMID 38260808.
  • v
  • t
  • e
Non-specific
AAADTooltip Aromatic L-amino acid decarboxylase
MAOTooltip Monoamine oxidase
Phenethylamines
(dopamine, epinephrine,
norepinephrine)
PAHTooltip Phenylalanine hydroxylase
THTooltip Tyrosine hydroxylase
DBHTooltip Dopamine beta-monooxygenase
PNMTTooltip Phenylethanolamine N-methyltransferase
  • Inhibitors: CGS-19281A
  • SKF-64139
  • SKF-7698
COMTTooltip Catechol-O-methyl transferase
Tryptamines
(serotonin, melatonin)
TPHTooltip Tryptophan hydroxylase
AANATTooltip Serotonin N-acetyl transferase
ASMTTooltip Acetylserotonin O-methyltransferase
Histamine
HDCTooltip Histidine decarboxylase
  • Substrates→Products: L-Histidine→Histamine
HNMTTooltip Histamine N-methyltransferase
  • Substrates→Products: Histamine→N-Methylhistamine
DAOTooltip Diamine oxidase
  • Substrates→Products: Histamine→Imidazole acetic acid
See also: Receptor/signaling modulators • Adrenergics • Dopaminergics • Melatonergics • Serotonergics • Monoamine reuptake inhibitors • Monoamine releasing agents • Monoamine neurotoxins
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