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It has been studied as a possible treatment for [[congestive heart failure]], and appears to be well tolerated as such.<ref>{{cite journal |vauthors=Hegde SS, Friday KF |title=Dopamine-beta-hydroxylase inhibition: a novel sympatho-modulatory approach for the treatment of congestive heart failure |journal=Current Pharmaceutical Design |volume=4 |issue=6 |pages=469–79 |date=December 1998 |doi=10.2174/138161280406221011113124 |pmid=10197057}}</ref> As of 2012, [[clinical trial]]s to assess nepicastat as a treatment for [[post-traumatic stress disorder]] (PTSD) and [[cocaine dependence]] have been completed.<ref>{{cite web |url=http://www.clinicaltrials.gov/ct2/show/NCT00641511 |title=Pharmacogenetic Clinical Trial of Nepicastat for Post Traumatic Stress Disorder (PTSD) |date=June 4, 2008 |publisher=U.S. [[National Institutes of Health]] |work=ClinicalTrials.gov}} Retrieved on February 1, 2012.</ref><ref>{{cite web |url=http://www.clinicaltrials.gov/ct2/show/NCT00656357 |title=Study of Safety and Potential Efficacy of SYN117 in Cocaine Dependent Volunteers |date=August 15, 2008 |publisher=U.S. [[National Institutes of Health]] |work=ClinicalTrials.gov}} Retrieved on February 1, 2012.</ref> 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.<ref>[http://www.biotie.com/en/investors/stock_exchange_releases/release/?NewsItemID=1667335&NewsItemYear=2012 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.</ref>
It has been studied as a possible treatment for [[congestive heart failure]], and appears to be well tolerated as such.<ref>{{cite journal |vauthors=Hegde SS, Friday KF |title=Dopamine-beta-hydroxylase inhibition: a novel sympatho-modulatory approach for the treatment of congestive heart failure |journal=Current Pharmaceutical Design |volume=4 |issue=6 |pages=469–79 |date=December 1998 |doi=10.2174/138161280406221011113124 |pmid=10197057}}</ref> As of 2012, [[clinical trial]]s to assess nepicastat as a treatment for [[post-traumatic stress disorder]] (PTSD) and [[cocaine dependence]] have been completed.<ref>{{cite web |url=http://www.clinicaltrials.gov/ct2/show/NCT00641511 |title=Pharmacogenetic Clinical Trial of Nepicastat for Post Traumatic Stress Disorder (PTSD) |date=June 4, 2008 |publisher=U.S. [[National Institutes of Health]] |work=ClinicalTrials.gov}} Retrieved on February 1, 2012.</ref><ref>{{cite web |url=http://www.clinicaltrials.gov/ct2/show/NCT00656357 |title=Study of Safety and Potential Efficacy of SYN117 in Cocaine Dependent Volunteers |date=August 15, 2008 |publisher=U.S. [[National Institutes of Health]] |work=ClinicalTrials.gov}} Retrieved on February 1, 2012.</ref> 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.<ref>[http://www.biotie.com/en/investors/stock_exchange_releases/release/?NewsItemID=1667335&NewsItemYear=2012 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.</ref>


Moreira-Rodrigues et al. have shown that mice without epinephrine have reduced contextual memory after fear conditioning.<ref>{{cite journal |vauthors=Alves E, Lukoyanov N, Serrão P, Moura D, Moreira-Rodrigues M |title= Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors.|date=2016 |journal=Psychopharmacology |volume=233 |issue=11 |pages=2099-2108. https://doi.org/10.1007/s00213-016-4254-5|doi= 10.1007/s00213-016-4254-5|pmid= 26935825}}</ref> In addition, in PTSD epinephrine strengthens traumatic contextual memory.<ref>{{Cite journal |last=Martinho |first=Raquel |last2=Oliveira |first2=Ana |last3=Correia |first3=Gabriela |last4=Marques |first4=Márcia |last5=Seixas |first5=Rafaela |last6=Serrão |first6=Paula |last7=Moreira-Rodrigues |first7=Mónica |date=2020-10-26 |title=Epinephrine May Contribute to the Persistence of Traumatic Memories in a Post-traumatic Stress Disorder Animal Model |url=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2020.588802/full |journal=Frontiers in Molecular Neuroscience |language=English |volume=13 |doi=10.3389/fnmol.2020.588802 |issn=1662-5099 |pmc=PMC7649334 |pmid=33192300}}</ref> Studies have shown that nepicastat effectively reduces norepinephrine in both peripheral and central tissues in rats<ref>{{Cite journal |last=Bonifácio |first=Maria João |last2=Sousa |first2=Filipa |last3=Neves |first3=Marco |last4=Palma |first4=Nuno |last5=Igreja |first5=Bruno |last6=Pires |first6=Nuno Miguel |last7=Wright |first7=Lyndon C. |last8=Soares-da-Silva |first8=Patrício |date=2015-03 |title=Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: Comparison with nepicastat |url=https://doi.org/10.1016/j.ejphar.2015.01.034 |journal=European Journal of Pharmacology |volume=751 |pages=50–58 |doi=10.1016/j.ejphar.2015.01.034 |issn=0014-2999}}</ref> <ref>{{Cite journal |last=Loureiro |first=Ana I. |last2=Bonifácio |first2=Maria João |last3=Fernandes-Lopes |first3=Carlos |last4=Pires |first4=Nuno |last5=Igreja |first5=Bruno |last6=Wright |first6=Lyndon C. |last7=Soares-da-Silva |first7=Patrício |date=2015-09-02 |title=Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat |url=http://www.tandfonline.com/doi/full/10.3109/00498254.2015.1018985 |journal=Xenobiotica |language=en |volume=45 |issue=9 |pages=828–839 |doi=10.3109/00498254.2015.1018985 |issn=0049-8254}}</ref>and dogs<ref>{{Cite journal |last=Stanley |first=William C. |last2=Li |first2=Bin |last3=Bonhaus |first3=Douglas W. |last4=Johnson |first4=Lowell G. |last5=Lee |first5=Keiho |last6=Porter |first6=Seth |last7=Walker |first7=Keith |last8=Martinez |first8=Greg |last9=Eglen |first9=Richard M. |last10=Whiting |first10=Roger L. |last11=Hegde |first11=Sharath S. |date=1997-08 |title=Catecholamine modulatory effects of nepicastat (RS‐25560‐197), a novel, potent and selective inhibitor of dopamine‐ β ‐hydroxylase |url=https://bpspubs.onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0701315 |journal=British Journal of Pharmacology |language=en |volume=121 |issue=8 |pages=1803–1809 |doi=10.1038/sj.bjp.0701315 |issn=0007-1188 |pmc=PMC1564872 |pmid=9283721}}</ref> . Nepicastat also increases the transcription Npas4 and Bdnf genes in the hippocampus which may play a role in neuronal regulation and weakening of traumatic contextual memories. <ref>{{Cite journal |last=Martinho |first=Raquel |last2=Correia |first2=Gabriela |last3=Seixas |first3=Rafaela |last4=Oliveira |first4=Ana |last5=Silva |first5=Soraia |last6=Serrão |first6=Paula |last7=Fernandes-Lopes |first7=Carlos |last8=Costa |first8=Cristina |last9=Moreira-Rodrigues |first9=Mónica |date=2021-09-24 |title=Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder |url=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.745219/full |journal=Frontiers in Molecular Neuroscience |language=English |volume=14 |doi=10.3389/fnmol.2021.745219 |issn=1662-5099 |pmc=PMC8498196 |pmid=34630037}}</ref><ref>{{Cite journal |last=Moreira-Rodrigues |first=Mónica |last2=Grubisha |first2=Melanie J. |date=2022-12-08 |title=Editorial: Molecular mechanisms of neuropsychiatric diseases |url=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.1102296/full |journal=Frontiers in Molecular Neuroscience |language=English |volume=15 |doi=10.3389/fnmol.2022.1102296 |issn=1662-5099 |pmc=PMC9773978 |pmid=36568276}}</ref> No DBH inhibitor has received marketing approval due to poor DBH selectivity, low potency and side effects, but DBH gene silencing may be an alternative for patients with increased sympathetic activity<ref>{{Cite journal |last=Azevedo |first=Márcia |last2=Martinho |first2=Raquel |last3=Oliveira |first3=Ana |last4=Correia-de-Sá |first4=Paulo |last5=Moreira-Rodrigues |first5=Mónica |date=2024-01-08 |title=Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder |url=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1332348/full |journal=Frontiers in Molecular Neuroscience |language=English |volume=16 |doi=10.3389/fnmol.2023.1332348 |issn=1662-5099 |pmc=PMC10800988 |pmid=38260808}}</ref>. However, some studies have shown that nepicastat can be well-tolerated in healthy adults and no differences in adverse events were observed<ref>{{Cite journal |last=De La Garza |first=Richard |last2=Bubar |first2=Marcy J. |last3=Carbone |first3=Crystal L. |last4=Moeller |first4=F. Gerard |last5=Newton |first5=Thomas F. |last6=Anastasio |first6=Noelle C. |last7=Harper |first7=Tod A. |last8=Ware |first8=David L. |last9=Fuller |first9=Michael A. |last10=Holstein |first10=Gaylyn J. |last11=Jayroe |first11=Jason B. |last12=Bandak |first12=Stephen I. |last13=Reiman |first13=Kirsten Z. |last14=Neale |first14=Ann C. |last15=Pickford |first15=Lesley B. |date=2015-06 |title=Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder |url=https://doi.org/10.1016/j.pnpbp.2015.01.009 |journal=Progress in Neuro-Psychopharmacology and Biological Psychiatry |volume=59 |pages=40–48 |doi=10.1016/j.pnpbp.2015.01.009 |issn=0278-5846 |pmc=PMC4777897 |pmid=25602710}}</ref>. Considering nepicastat  treatment has been proven to be effective in reducing signs in PTSD mice model with increased catecholamine levels<ref>{{Cite journal |last=Martinho |first=Raquel |last2=Correia |first2=Gabriela |last3=Seixas |first3=Rafaela |last4=Oliveira |first4=Ana |last5=Silva |first5=Soraia |last6=Serrão |first6=Paula |last7=Fernandes-Lopes |first7=Carlos |last8=Costa |first8=Cristina |last9=Moreira-Rodrigues |first9=Mónica |date=2021-09-24 |title=Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder |url=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.745219/full |journal=Frontiers in Molecular Neuroscience |language=English |volume=14 |doi=10.3389/fnmol.2021.745219 |issn=1662-5099 |pmc=PMC8498196 |pmid=34630037}}</ref>. Therefore, Nepicastat can be an efficent treatment at least in humans with PTSD that have increased catecholamine plasma levels.
Moreira-Rodrigues et al. have shown that mice without epinephrine have reduced contextual memory after fear conditioning.<ref>{{cite journal |vauthors=Alves E, Lukoyanov N, Serrão P, Moura D, Moreira-Rodrigues M |title= Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors.|date=2016 |journal=Psychopharmacology |volume=233 |issue=11 |pages=2099-2108. https://doi.org/10.1007/s00213-016-4254-5|doi= 10.1007/s00213-016-4254-5|pmid= 26935825}}</ref>


==References==
==References==

Revision as of 11:48, 15 July 2024

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
3D model (JSmol)
ChEBI
ChemSpider
MeSH Nepicastat
UNII
  • 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
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).
checkY verify (what is checkY☒N ?)

Nepicastat (INN, codenamed SYN117, RS-25560-197) is an inhibitor of dopamine beta-hydroxylase, 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]

Moreira-Rodrigues et al. have shown that mice without epinephrine have reduced contextual memory after fear conditioning.[6] In addition, in PTSD epinephrine strengthens traumatic contextual memory.[7] Studies have shown that nepicastat effectively reduces norepinephrine in both peripheral and central tissues in rats[8] [9]and dogs[10] . Nepicastat also increases the transcription Npas4 and Bdnf genes in the hippocampus which may play a role in neuronal regulation and weakening of traumatic contextual memories. [11][12] No DBH inhibitor has received marketing approval due to poor DBH selectivity, low potency and side effects, but DBH gene silencing may be an alternative for patients with increased sympathetic activity[13]. However, some studies have shown that nepicastat can be well-tolerated in healthy adults and no differences in adverse events were observed[14]. Considering nepicastat  treatment has been proven to be effective in reducing signs in PTSD mice model with increased catecholamine levels[15]. Therefore, Nepicastat can be an efficent treatment at least in humans with PTSD that have increased catecholamine plasma levels.

References

  1. ^ Stanley WC, Li B, Bonhaus DW, et al. (August 1997). "Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase". Br J Pharmacol. 121 (8): 1803–9. 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): 469–79. 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 (2016). "Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors". Psychopharmacology. 233 (11): 2099-2108. https://doi.org/10.1007/s00213-016-4254-5. doi:10.1007/s00213-016-4254-5. PMID 26935825.
  7. ^ Martinho, Raquel; Oliveira, Ana; Correia, Gabriela; Marques, Márcia; Seixas, Rafaela; Serrão, Paula; Moreira-Rodrigues, Mónica (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. doi:10.3389/fnmol.2020.588802. ISSN 1662-5099. PMC 7649334. PMID 33192300.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  8. ^ Bonifácio, Maria João; Sousa, Filipa; Neves, Marco; Palma, Nuno; Igreja, Bruno; Pires, Nuno Miguel; Wright, Lyndon C.; Soares-da-Silva, Patrício (2015-03). "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. ISSN 0014-2999. {{cite journal}}: Check date values in: |date= (help)
  9. ^ Loureiro, Ana I.; Bonifácio, Maria João; Fernandes-Lopes, Carlos; Pires, Nuno; Igreja, Bruno; Wright, Lyndon C.; Soares-da-Silva, Patrício (2015-09-02). "Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat". Xenobiotica. 45 (9): 828–839. doi:10.3109/00498254.2015.1018985. ISSN 0049-8254.
  10. ^ Stanley, William C.; Li, Bin; Bonhaus, Douglas W.; Johnson, Lowell G.; Lee, Keiho; Porter, Seth; Walker, Keith; Martinez, Greg; Eglen, Richard M.; Whiting, Roger L.; Hegde, Sharath S. (1997-08). "Catecholamine modulatory effects of nepicastat (RS‐25560‐197), a novel, potent and selective inhibitor of dopamine‐ β ‐hydroxylase". British Journal of Pharmacology. 121 (8): 1803–1809. doi:10.1038/sj.bjp.0701315. ISSN 0007-1188. PMC 1564872. PMID 9283721. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  11. ^ Martinho, Raquel; Correia, Gabriela; Seixas, Rafaela; Oliveira, Ana; Silva, Soraia; Serrão, Paula; Fernandes-Lopes, Carlos; Costa, Cristina; Moreira-Rodrigues, Mónica (2021-09-24). "Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder". Frontiers in Molecular Neuroscience. 14. doi:10.3389/fnmol.2021.745219. ISSN 1662-5099. PMC 8498196. PMID 34630037.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  12. ^ Moreira-Rodrigues, Mónica; Grubisha, Melanie J. (2022-12-08). "Editorial: Molecular mechanisms of neuropsychiatric diseases". Frontiers in Molecular Neuroscience. 15. doi:10.3389/fnmol.2022.1102296. ISSN 1662-5099. PMC 9773978. PMID 36568276.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  13. ^ Azevedo, Márcia; Martinho, Raquel; Oliveira, Ana; Correia-de-Sá, Paulo; Moreira-Rodrigues, Mónica (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. doi:10.3389/fnmol.2023.1332348. ISSN 1662-5099. PMC 10800988. PMID 38260808.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  14. ^ De La Garza, Richard; Bubar, Marcy J.; Carbone, Crystal L.; Moeller, F. Gerard; Newton, Thomas F.; Anastasio, Noelle C.; Harper, Tod A.; Ware, David L.; Fuller, Michael A.; Holstein, Gaylyn J.; Jayroe, Jason B.; Bandak, Stephen I.; Reiman, Kirsten Z.; Neale, Ann C.; Pickford, Lesley B. (2015-06). "Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 59: 40–48. doi:10.1016/j.pnpbp.2015.01.009. ISSN 0278-5846. PMC 4777897. PMID 25602710. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  15. ^ Martinho, Raquel; Correia, Gabriela; Seixas, Rafaela; Oliveira, Ana; Silva, Soraia; Serrão, Paula; Fernandes-Lopes, Carlos; Costa, Cristina; Moreira-Rodrigues, Mónica (2021-09-24). "Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder". Frontiers in Molecular Neuroscience. 14. doi:10.3389/fnmol.2021.745219. ISSN 1662-5099. PMC 8498196. PMID 34630037.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)


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