Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB‐1020: Implications for treatment of attention‐deficit hyperactivity disorder

  title={Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB‐1020: Implications for treatment of attention‐deficit hyperactivity disorder},
  author={Frank P. Bymaster and Krystyna Gołembiowska and Magdalena Kowalska and Yong Kee Choi and Frank I. Tarazi},
We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB‐1020 (1R,5S)‐1‐(naphthalen‐2‐yl)‐3‐azabicyclo[3.1.0]hexane HCl). EB‐1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC50 values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB‐1020 markedly increased NE, and DA concentrations levels in rat… 

Tph2 gene deletion enhances amphetamine‐induced hypermotility: effect of 5‐HT restoration and role of striatal noradrenaline release

It was found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2−/− mice and this findings indicate that amphetamine‐induced hyperactivity is attenuated by endogenous 5‐HT through the inhibition of striatal NA release.

Novel Potent Dopamine-Norepinephrine and Triple Reuptake Uptake Inhibitors Based on Asymmetric Pyran Template and Their Molecular Interactions with Monoamine Transporters.

A significant influence from the alteration of the stereochemistry of the hydroxyl group on the pyran ring of D-473 on transporters affinities was observed indicating stereospecific preference for interaction.

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges.

The successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability, as well as therapeutic potential for other indications.

Noradrenergic reuptake inhibition in the treatment of pain

  • C. Hartrick
  • Biology, Medicine
    Expert opinion on investigational drugs
  • 2012
The intrathecal delivery of noradrenergic reuptake inhibitors, allowing delivery directly to the central nervous system thus limiting systemic exposure, represents an exciting avenue of investigation.

The safety of extended-release drug formulations for the treatment of ADHD

Limitations of currently marketed medications have led to the search for drugs with efficacy comparable to ER stimulants and a more favorable adverse event profile and several are in development, but their potential utility is not yet known.

Triple reuptake inhibitors as potential next-generation antidepressants: a new hope?

The current review comprehensively describes the development ofTRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.



Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677

DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.

Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors.

  • J. CryanO. O'Leary I. Lucki
  • Psychology, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2004
Restoration of NE by using L-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh(-/-) mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency.

Atomoxetine blocks motor hyperactivity in neonatal 6-hydroxydopamine-lesioned rats: implications for treatment of attention-deficit hyperactivity disorder.

We recently reported that selective inhibitors of neuronal transport of norepinephrine (NE), desipramine and nisoxetine, reversed motor hyperactivity in an animal model of attention-deficit

Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats.

The findings indicate that behavioral effects of stimulants in young rats with neonatal 6-OHDA lesions may be mediated by release of NE or 5-HT and support interest in using drugs that increase activity of norepinephrine or serotonin to treat ADHD.

Dual serotonin and noradrenaline uptake inhibitor class of antidepressants potential for greater efficacy or just hype?

  • D. WongF. Bymaster
  • Psychology, Biology
    Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques
  • 2002
Comparative trials of dual uptake inhibitors against the other agents are needed to establish whether the dual uptake inhibitor show improvement in efficacy, rate of responders, antidepressive effects and/or remission.

Subjective and Objective Effects of the Novel Triple Reuptake Inhibitor Tesofensine in Recreational Stimulant Users

The study results show that the effects of D‐amphetamine were significantly greater than those of placebo on all primary and secondary subjective measures and tesofensine is therefore unlikely to be recreationally abused.

Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse.

  • J. ZhuM. Reith
  • Biology, Psychology
    CNS & neurological disorders drug targets
  • 2008
Current knowledge of multiple factors regulating DAT activity has greatly expanded, and many aspects of this regulation remain to be elucidated; these data will enable efforts to identify drugs that might be used therapeutically for drug dependence therapeutics.

Blockade of the Noradrenaline Carrier Increases Extracellular Dopamine Concentrations in the Prefrontal Cortex: Evidence that Dopamine Is Taken up In Vivo by Noradrenergic Terminals

It is suggested that reuptake into NA terminals is an important mechanism by which DA is cleared from the extracellular space in a NA‐rich area such as the prefrontal cortex and may play a role in the therapeutic effects of these drugs.