Dasotraline [(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine] is a new serotonin [5-hydroxytryptamine (5-HT)], dopamine (DA) and norepinephrine (NE) reuptake inhibitor (SDNRI),
which blocks pre-synaptic dopamine transporters to increase their levels in the
brain. For this unique three sided attack, it is a so-called a triple reuptake
inhibitor (TRI). Triple reuptake inhibitors represent a potential new class of
antidepressant drugs that block norepinephrine, dopamine and serotonin transporters.
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| Dasotraline: 2D and 3D Structure |
Dasotraline
is an antidepressant which had been in early clinical trials at Sepracor (now
Sunovion Pharmaceuticals) for the treatment of major depressive disorder (MDD).
In 2010, the company discontinued development of the compound for this
indication. At present, phase II clinical trials are under way for the
treatment of attention deficit/hyperactivity disorder (ADHD). In preclinical
studies, the drug has been shown to be a potent and balanced reuptake inhibitor
of serotonin, norepinephrine and dopamine. A drug candidate with a triple
mechanism of action as such may provide a broader spectrum of therapy than
currently marketed antidepressants. Sunovion has also planned clinical trials
to evaluate the drug’s safety and usefulness in treating children with ADHD.
Common Name: Dasotraline
Synonyms: SEP-225289;
SEP225289; SEP 225289
IUPAC Name: (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
CAS Number: 675126-05-3
Mechanism of Action: Triple Reuptake Inhibitor
Indication: Treatment of Attention Deficit Hyperactivity Disorder; Treatment of ADHD
Development Stage: Phase I/II
Company: Sunovion Pharmaceuticals
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| 1H NMR (Estimated) for Dasotraline |
Early Study
The double-blind clinical trial ran for four
weeks, and measured symptoms against the ADHD Rating Scale-IV, which tracks the
frequency of DSM-IV criteria like hyperactivity, impulsivity, and
inattentiveness. The ADHD adults who participated were randomly assigned doses
of 4 mg/daily, 8 mg/daily, or a placebo. The results showed a significant
improvement in symptoms for the 8 mg dosage, and some improvement with the 4 mg
dosage. Some participants experienced side effects, including insomnia,
anxiety, and panic attacks.
PET Study
SEP-225289 is a novel compound that, based on in vitro potencies
for transporter function, potentially inhibits reuptake at dopamine,
norepinephrine, and serotonin transporters. An open-label PET study was
conducted during the development of SEP-225289 to investigate its dopamine and serotonin
transporter occupancy [1].
Methodology
Different single doses of SEP-225289 were administered to healthy
volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET
was performed before and approximately 24 h after oral administration of
SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin
transporter occupancies were estimated from PET using
(11)C-N-(3-iodoprop-2E-enyl)-2ß-carbomethoxy-3ß-(4-methylphenyl)nortropane
((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine
((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed
before ligand injection, and subjects were monitored for adverse events.
Results
Average dopamine and serotonin transporter occupancies increased
with increasing doses of SEP-225289. Mean dopamine and serotonin transporter
occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and
9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively,
for 16 mg. On the basis of the relationship between occupancy and plasma
concentration, dopamine transporter IC50 was determined (4.5 ng/mL)
and maximum dopamine transporter occupancy was extrapolated (85%).
References:
1. DeLorenzo, C.; et. al. SEP-225289 serotonin and dopamine
transporter occupancy: a PET study. J Nucl Med 2011, 52(7), 1150-1155.
2. ClinicalTrials.gov Open-label Safety Study in
Adults With ADHD. NCT02160262 (retrieved 01-05-2015)
3. ClinicalTrials.gov Adult Attention Deficit
Hyperactivity Disorder. NCT01692782 (retrieved 01-05-2015)
4. ClinicalTrials.gov Dasotraline Pediatric ADHD Study. NCT02428088 (retrieved 01-05-2015)
