Chemistry:Nepicastat

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Nepicastat (INN; developmental code names SYN117, RS-25560-197) is an inhibitor of dopamine β-hydroxylase (DBH), an enzyme that catalyzes the conversion of dopamine to norepinephrine.[1][2]

It has been studied as a possible treatment for congestive heart failure, and appears to be well tolerated as such.[3] As of 2012, clinical trials to assess nepicastat as a treatment for post-traumatic stress disorder (PTSD) and cocaine dependence have been completed.[4][5] 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.[6] As of October 2024, development has been discontinued for most indications.[1]

Mice lacking epinephrine exhibit reduced contextual memory after fear conditioning .[7] In addition, in PTSD epinephrine enhances traumatic contextual memory.[8] Studies indicate that nepicastat effectively reduces norepinephrine in both peripheral and central tissues in rats[9][10] and dogs.[11] 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 [12][13] 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.[14] Some studies, however have shown that nepicastat is well-tolerated in healthy adults and no significant differences in adverse events were observed.[15] Given that nepicastat treatment has been proven to be effective in reducing signs in an PTSD mouse model with increased catecholamine levels,[16] it could be a promising treatment option for humans with PTSD characterized by increased catecholamine plasma levels.[17]

See also

References

  1. ↑ 1.0 1.1 "Nepicastat oral- Asieris Pharmaceuticals". 7 October 2024. https://adisinsight.springer.com/drugs/800025587. 
  2. ↑ "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. August 1997. doi:10.1038/sj.bjp.0701315. PMID 9283721. 
  3. ↑ "Dopamine-beta-hydroxylase inhibition: a novel sympatho-modulatory approach for the treatment of congestive heart failure". Current Pharmaceutical Design 4 (6): 469–479. December 1998. doi:10.2174/138161280406221011113124. PMID 10197057. 
  4. ↑ "Pharmacogenetic Clinical Trial of Nepicastat for Post Traumatic Stress Disorder (PTSD)". ClinicalTrials.gov (U.S. National Institutes of Health). June 4, 2008. http://www.clinicaltrials.gov/ct2/show/NCT00641511.  Retrieved on February 1, 2012.
  5. ↑ "Study of Safety and Potential Efficacy of SYN117 in Cocaine Dependent Volunteers". ClinicalTrials.gov (U.S. National Institutes of Health). August 15, 2008. http://www.clinicaltrials.gov/ct2/show/NCT00656357.  Retrieved on February 1, 2012.
  6. ↑ 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.
  7. ↑ "Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors". Psychopharmacology 233 (11): 2099–2108. June 2016. doi:10.1007/s00213-016-4254-5. PMID 26935825. 
  8. ↑ "Epinephrine May Contribute to the Persistence of Traumatic Memories in a Post-traumatic Stress Disorder Animal Model" (in English). Frontiers in Molecular Neuroscience 13. 2020-10-26. doi:10.3389/fnmol.2020.588802. PMID 33192300. 
  9. ↑ "Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: comparison with nepicastat". European Journal of Pharmacology 751: 50–58. March 2015. doi:10.1016/j.ejphar.2015.01.034. PMID 25641750. 
  10. ↑ "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. 2015-09-02. doi:10.3109/00498254.2015.1018985. PMID 25915108. 
  11. ↑ "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. August 1997. doi:10.1038/sj.bjp.0701315. PMID 9283721. 
  12. ↑ "Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder" (in English). Frontiers in Molecular Neuroscience 14. 2021-09-24. doi:10.3389/fnmol.2021.745219. PMID 34630037. 
  13. ↑ "Editorial: Molecular mechanisms of neuropsychiatric diseases" (in English). Frontiers in Molecular Neuroscience 15. 2022-12-08. doi:10.3389/fnmol.2022.1102296. PMID 36568276. 
  14. ↑ "Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder" (in English). Frontiers in Molecular Neuroscience 16. 2024-01-08. doi:10.3389/fnmol.2023.1332348. PMID 38260808. 
  15. ↑ "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. June 2015. doi:10.1016/j.pnpbp.2015.01.009. PMID 25602710. 
  16. ↑ "Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder" (in English). Frontiers in Molecular Neuroscience 14. 2021-09-24. doi:10.3389/fnmol.2021.745219. PMID 34630037. 
  17. ↑ "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. 2024-01-08. doi:10.3389/fnmol.2023.1332348. PMID 38260808. 



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