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Nepicastat
Chemical compound From Wikipedia, the free encyclopedia
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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]
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