| Candidate ID: | R0198 |
| Source ID: | DB00574 |
| Source Type: | approved; illicit; investigational; withdrawn |
| Compound Type: |
small molecule
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| Compound Name: |
Fenfluramine
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| Synonyms: |
(±)-fenfluramine; 1-(m-trifluoromethyl-phenyl)-2-ethylaminopropane; DL-Fenfluramine; Fenfluramina; Fenfluramine
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| Molecular Formula: |
C12H16F3N
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| SMILES: |
CCNC(C)CC1=CC=CC(=C1)C(F)(F)F
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| Structure: |
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| DrugBank Description: |
Dravet syndrome is a pediatric encephalopathy that typically manifests within the first year of life following exposure to elevated temperatures. It is characterized by recurrent pharmacoresistant seizures, which increase in frequency and severity with disease progression. Concomitantly with these seizures, patients typically display delayed development and neurocognitive impairment. Fenfluramine is a serotonergic phenethylamine originally used as an appetite suppressant until concerns regarding cardiotoxicity in obese patients lead to its withdrawal from the market in 1997. Through its ability to modulate neurotransmission, fenfluramine has reemerged as an effective therapy against pharmacoresistant seizures, such as those involved in Dravet syndrome.
Fenfluramine was granted initial FDA approval in 1973 prior to its withdrawal; it was granted a new FDA approval on June 25, 2020, for treatment of Dravet syndrome patients through the restricted FINTEPLA REMS program. It is currently sold under the name FINTEPLA® by Zogenix INC.
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| CAS Number: |
458-24-2
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| Molecular Weight: |
231.2573
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| DrugBank Indication: |
Fenfluramine is indicated for the treatment of seizures in Dravet syndrome patients aged two years and older.
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| DrugBank Pharmacology: |
Fenfluramine increases extracellular serotonin levels, and also acts as both a serotonergic 5-HT<sub>2</sub> receptor agonist and σ1 receptor antagonist. These activities, through an incompletely understood mechanism, lead to anti-epileptiform activity and therapeutic benefit. This modulation has other effects such as decreased appetite, weight loss, sedation, lethargy, increased blood pressure, and mood alteration including possible suicidal ideation. There is a risk of glaucoma and potentially fatal serotonin syndrome. Fenfluramine should be gradually withdrawn following treatment alteration or cessation.
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| DrugBank MoA: |
Dravet syndrome is a complex pediatric encephalopathy characterized by recurrent pharmacoresistant seizures of variable type, delayed development, and in many cases, impairment in speech, language, gait, and other neurocognitive functions. Despite substantial variation in presentation and severity, roughly 80% of patients with Dravet syndrome have mutations in the _SCN1A_ gene, which encodes the alpha subunit of a voltage-gated sodium channel (Na<sub>v</sub>1.1). This channel is predominantly localized in inhibitory GABAergic interneurons as well as in excitatory pyramidal neurons; it is thought that dysfunction of neurotransmission regulation results in the seizures and other corresponding symptoms of Dravet syndrome.
Various _in vitro_ and _in vivo_ studies have demonstrated that fenfluramine is capable of acting as an agonist of multiple serotonin receptors including 5-HT<sub>1A</sub>, 5-HT<sub>1D</sub>, 5-HT<sub>2A</sub>, 5-HT<sub>2B</sub>, and 5-HT<sub>2C</sub>, as well as a σ1 receptor antagonist. This is at least partly because fenfluramine, as well as its active metabolite norfenfluramine, can act on sodium-dependent serotonin transporters (SERTs) to reverse transport direction and thereby increase extracellular serotonin levels. However, work in animal models of Dravet syndrome suggest that only the modulation of 5-HT<sub>1D</sub>, 5-HT<sub>2C</sub>, σ1, and possibly 5-HT<sub>2A</sub> receptors of fenfluramine result in the anti-epileptiform activity. Interestingly, 5-HT<sub>2B</sub> receptor agonism, which had previously been associated with cardiac valvulopathy, is not anticipated to have any therapeutic value in Dravet syndrome.
Although the exact mechanism by which stimulation/inhibition of various receptors leads to the observed therapeutic benefit is unclear, it is hypothesized to be two-fold. Stimulation of 5-HT<sub>1D</sub> and 5-HT<sub>2C</sub> may result in increased GABAergic neurotransmission, while σ1 receptor antagonism may help to modulate responses to _N_-methyl-D-aspartate (NMDA).
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| Targets: |
Sodium-dependent serotonin transporter substrate&inhibitor; 5-hydroxytryptamine receptor 1D agonist; 5-hydroxytryptamine receptor 2C agonist; Sigma non-opioid intracellular receptor 1 antagonist; 5-hydroxytryptamine receptor 2A agonist; 5-hydroxytryptamine receptor 2B agonist; 5-hydroxytryptamine receptor 1A agonist
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| Inclusion Criteria: |
Therapeutic strategy associated
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