Nepicastat

Last updated
Nepicastat
Nepicastat Structure.svg
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
PubChem CID
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 Yes check.svgY
    Key: YZZVIKDAOTXDEB-JTQLQIEISA-N Yes check.svgY
  • 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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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]

Related Research Articles

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that develops from experiencing a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a person's life or well-being. Symptoms may include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in the way a person thinks and feels, and an increase in the fight-or-flight response. These symptoms last for more than a month after the event. Young children are less likely to show distress, but instead may express their memories through play. A person with PTSD is at a higher risk of suicide and intentional self-harm.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Adrenal medulla</span> Central part of the adrenal gland

The adrenal medulla is the inner part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of chromaffin cells that secrete catecholamines, including epinephrine (adrenaline), norepinephrine (noradrenaline), and a small amount of dopamine, in response to stimulation by sympathetic preganglionic neurons.

<span class="mw-page-title-main">Fear conditioning</span> Behavioral paradigm in which organisms learn to predict aversive events

Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus is associated with a particular neutral context or neutral stimulus, resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus. Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).

Neurochemistry is the study of chemicals, including neurotransmitters and other molecules such as psychopharmaceuticals and neuropeptides, that control and influence the physiology of the nervous system. This particular field within neuroscience examines how neurochemicals influence the operation of neurons, synapses, and neural networks. Neurochemists analyze the biochemistry and molecular biology of organic compounds in the nervous system, and their roles in such neural processes including cortical plasticity, neurogenesis, and neural differentiation.

Acute stress reaction and acute stress disorder (ASD) is a psychological response to a terrifying, traumatic or surprising experience. Combat stress reaction (CSR) is a similar response to the trauma of war. The reactions may include but are not limited to intrusive or dissociative symptoms, and reactivity symptoms such as avoidance or arousal. It may be exhibited for days or weeks after the traumatic event. If the condition is not correctly addressed, it may develop into post-traumatic stress disorder (PTSD).

α-Methyl-<i>p</i>-tyrosine Chemical compound

α-Methyl-p-tyrosine (AMPT), or simply α-methyltyrosine, also known in its chiral 2-(S) form as metirosine, is a tyrosine hydroxylase enzyme inhibitor and is therefore a drug involved in inhibiting the catecholamine biosynthetic pathway. AMPT inhibits tyrosine hydroxylase whose enzymatic activity is normally regulated through the phosphorylation of different serine residues in regulatory domain sites. Catecholamine biosynthesis starts with dietary tyrosine, which is hydroxylated by tyrosine hydroxylase and it is hypothesized that AMPT competes with tyrosine at the tyrosine-binding site, causing inhibition of tyrosine hydroxylase.

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzyme found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

<span class="mw-page-title-main">Norepinephrine</span> Catecholamine hormone and neurotransmitter

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" is more commonly used in the United Kingdom, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

A sympatholytic (sympathoplegic) drug is a medication that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system (SNS). They are indicated for various functions; for example, they may be used as antihypertensives. They are also used to treat anxiety, such as generalized anxiety disorder, panic disorder and PTSD. In some cases, such as with guanfacine, they have also shown to be beneficial in the treatment of ADHD.

<span class="mw-page-title-main">Dopamine beta-hydroxylase</span> Mammalian protein found in Homo sapiens

Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.

Prolonged exposure therapy (PE) is a form of behavior therapy and cognitive behavioral therapy designed to treat post-traumatic stress disorder. It is characterized by two main treatment procedures – imaginal and in vivo exposures. Imaginal exposure is repeated 'on-purpose' retelling of the trauma memory. In vivo exposure is gradually confronting situations, places, and things that are reminders of the trauma or feel dangerous. Additional procedures include processing of the trauma memory and breathing retraining.

Memory and trauma is the deleterious effects that physical or psychological trauma has on memory.

<span class="mw-page-title-main">Adrenaline</span> Hormone and medication

Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions. It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and by a small number of neurons in the medulla oblongata. It plays an essential role in the fight-or-flight response by increasing blood flow to muscles, heart output by acting on the SA node, pupil dilation response, and blood sugar level. It does this by binding to alpha and beta receptors. It is found in many animals, including humans, and some single-celled organisms. It has also been isolated from the plant Scoparia dulcis found in Northern Vietnam.

<span class="mw-page-title-main">Dopamine beta hydroxylase deficiency</span> Medical condition

Dopamine beta (β)-hydroxylase deficiency is a human medical condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine.

PTSD or post-traumatic stress disorder, is a psychiatric disorder characterised by intrusive thoughts and memories, dreams or flashbacks of the event; avoidance of people, places and activities that remind the individual of the event; ongoing negative beliefs about oneself or the world, mood changes and persistent feelings of anger, guilt or fear; alterations in arousal such as increased irritability, angry outbursts, being hypervigilant, or having difficulty with concentration and sleep.

The TH gene codes for the enzyme tyrosine hydroxylase.

Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.

MDMA-assisted psychotherapy is the use of prescribed doses of MDMA as an adjunct to psychotherapy sessions. Research suggests that MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), including Complex PTSD, might improve treatment effectiveness. In 2017, a Phase II clinical trial led to "breakthrough therapy" designation by the US Food and Drug Administration (FDA) for potential use as a treatment for PTSD.

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.