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 ?)
Infobox references

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]

Related Research Articles

Post-traumatic stress disorder mental disorder that can develop after experiencing or witnessing a terrifying or life-threatening event

Post-traumatic stress disorder (PTSD) is a mental disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, or other threats on a person's life. 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.

Sertraline Antidepressant medication

Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants, and it may work better than fluoxetine for some subtypes of depression. Sertraline is effective for panic disorder, social anxiety disorder, generalized anxiety disorder, and obsessive–compulsive disorder (OCD). However, for OCD, cognitive behavioral therapy, particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder, sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.

Phenelzine Antidepressant

Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use. It is taken by mouth.

Nightmare disorder Medical condition

Nightmare disorder, also known as dream anxiety disorder, is a sleep disorder characterized by frequent nightmares. The nightmares, which often portray the individual in a situation that jeopardizes their life or personal safety, usually occur during the REM stages of sleep. Though most people have experienced at least one nightmare during their life, subjects with nightmare disorder experience them with a greater frequency. The disorder's DSM-IV number is 307.47.

Norepinephrine reuptake inhibitor

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

Eye movement desensitization and reprocessing (EMDR) is a form of psychotherapy developed by Francine Shapiro starting in 1988 in which the person being treated is asked to recall distressing images; the therapist then directs the patient in one type of bilateral stimulation, such as side-to-side eye rapid movement or hand tapping. According to the 2013 World Health Organization practice guideline: "This therapy [EMDR] is based on the idea that negative thoughts, feelings and behaviours are the result of unprocessed memories. The treatment involves standardized procedures that include focusing simultaneously on (a) spontaneous associations of traumatic images, thoughts, emotions and bodily sensations and (b) bilateral stimulation that is most commonly in the form of repeated eye movements."

AMPT

Alpha-methyl-p-tyrosine (AMPT) 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.

Dopaminergic Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

Complex post-traumatic stress disorder is a psychological disorder that can develop in response to prolonged, repeated experience of interpersonal trauma in a context in which the individual has little or no chance of escape. C-PTSD relates to the trauma model of mental disorders and is associated with chronic sexual, psychological, and physical abuse or neglect, chronic intimate partner violence, victims of prolonged workplace or school bullying, victims of kidnapping and hostage situations, indentured servants, victims of slavery and human trafficking, sweatshop workers, prisoners of war, concentration camp survivors, residential school survivors, prisoners kept in solitary confinement for a long period of time, and defectors from authoritarian religions. It is most often directed at children and emotionally vulnerable adults, and whilst motivations behind such abuse vary, though mostly being predominantly malicious, it has also been shown that the motivations behind such abuse can be well-intentioned. Situations involving captivity/entrapment can lead to C-PTSD-like symptoms, which can include prolonged feelings of terror, worthlessness, helplessness, and deformation of one's identity and sense of self.

A sympatholytic 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.

Biotie Therapies

Biotie Therapies was a Finnish biotechnology and pharmaceutics company that was acquired by Acorda Therapeutics in January 2016. The company's research and development was focused on drugs for neurodegenerative and psychiatric disorders like Parkinson's disease, Alzheimer's disease and other cognitive disorders, alcohol and drug dependence and post traumatic stress disorder, and inflammatory and fibrotic liver disease. The company's headquarters is in Turku, Western Finland, and it is listed on NASDAQ OMX Helsinki.

Dopamine beta-hydroxylase

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.

Dopamine beta hydroxylase deficiency Medical condition

Dopamine beta (β)-hydroxylase deficiency is a condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine. Dopamine is released, as a false neurotransmitter, in place of norepinephrine. Other names for norepinephrine include noradrenaline (NA) and noradrenalin. This condition is also sometimes referred to as "norepinephrine deficiency". Researchers of disorders such as schizophrenia are interested in studying this disorder, as patients with these specific diseases can have an increase in the amount of dopamine in their system and yet do not show other symptoms of DβH deficiency.

NS-2359

NS-2359 (GSK-372,475) is a serotonin-norepinephrine-dopamine reuptake inhibitor. It was under development by GlaxoSmithKline (GSK) as an antidepressant, but was discontinued in 2009 when phase II clinical trials turned up disappointing results and did not support further effort by the company. NS-2359 was also in clinical trials for the treatment of ADHD, phase II having been completed in 2007. A trial exploring the effect of NS-2359 on cocaine-dependent individuals is currently ongoing.

PTSD is a psychiatric disorder characterized 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. PTSD is commonly treated with various types of psychotherapy and pharmacotherapy.

Centanafadine

Centanafadine (INN) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) that began its development with Euthymics Bioscience after they acquired DOV Pharmaceutical. It was developed as a treatment for attention-deficit hyperactivity disorder (ADHD) and inhibits the reuptake of norepinephrine, dopamine, and serotonin with a ratio of 1:6:14, respectively. In 2011, Euthymics Bioscience spun off its development of centanafadine to a new company called Neurovance. In March 2017, Otsuka Pharmaceutical acquired Neurovance and the rights to centanafadine. As of January 2018, Otsuka's pipeline indicates it is in Phase III clinical trials.

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.

Post-traumatic stress disorder (PTSD) can affect about 3.6% of the U.S. population each year, and 6.8% of the U.S. population over a lifetime. 8.4% of people in the U.S. are diagnosed with substance use disorders (SUD). Of those with a diagnosis of PTSD, a co-occurring, or comorbid diagnosis of a SUD is present in 20–35% of that clinical population.

MDMA-assisted psychotherapy is the use of prescribed doses of MDMA as an adjunct to psychotherapy sessions. The study of MDMA as an enhancer for psychotherapy has been constrained since 1985 when the drug was classified in the United States as a Schedule I controlled substance. Research by the Multidisciplinary Association for Psychedelic Studies (MAPS) has provided evidence that MDMA can help address trauma-related disease, in particular post-traumatic stress disorder. In 2017, a Phase II clinical trial led to a designation of breakthrough therapy status by the US Food and Drug Administration (FDA).

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. 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.