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NS-2359 (GSK372475) is a triple monoamine reuptake inhibitor with approximately equipotent blockade of the dopamine, norepinephrine, and serotonin transporters, originally developed by NeuroSearch and licensed to GlaxoSmithKline [1]. It was investigated as a broad-spectrum antidepressant and for other neuropsychiatric indications, but two controlled trials in major depressive disorder found it neither efficacious nor well tolerated [1].
- Potent, balanced inhibition of dopamine, norepinephrine, and serotonin reuptake, of interest for probing monoaminergic pharmacology
- Well-characterized clinical pharmacology and a documented human safety profile from controlled trials
- Dry mouth, insomnia, anxiety, nausea, and tachycardia occurred more often than placebo
- Increases in heart rate and blood pressure; no antidepressant efficacy demonstrated
Overview
Triple reuptake inhibitors (TRIs), sometimes called 'serotonin-norepinephrine-dopamine reuptake inhibitors,' were pursued on the rationale that simultaneously raising all three monoamines might yield faster or more complete antidepressant effects than agents acting on one or two transporters. NS-2359 is a frequently modeled representative of this class and has been used in computational studies of transporter binding selectivity [2].
In two randomized, placebo- and active-controlled ten-week studies in outpatients with major depressive disorder, GSK372475 at 1 to 2 mg per day did not separate from placebo on any key efficacy endpoint, whereas the active comparators venlafaxine and paroxetine did. Adverse effects were more frequent than placebo, including dry mouth, insomnia, anxiety, gastrointestinal complaints, and tachycardia, with greater increases in heart rate and blood pressure and lower study completion rates [1]. The compound was also explored for attention-deficit/hyperactivity disorder and cocaine dependence in the broader development literature.
NS-2359 is not an approved medicine and is supplied for laboratory research only. Its clinical record illustrates that potent triple monoamine reuptake inhibition does not reliably translate into antidepressant benefit and can carry cardiovascular and tolerability costs.
- NS-2359 blocks the dopamine, norepinephrine, and serotonin transporters with roughly equal potency, a rare 'balanced' triple reuptake profile.
- Despite strong theoretical appeal, it failed to beat placebo in two major depression trials while venlafaxine and paroxetine succeeded.
- It is a favorite model compound in computational studies of monoamine-transporter selectivity.
Mechanism
NS-2359 inhibits the reuptake of , , and by binding their respective plasma-membrane transporters (, NET, SERT) with roughly equipotent activity, thereby increasing concentrations of all three monoamines [1][2]. Because these transporters share a high degree of structural homology at the substrate site, achieving a defined ratio of activity across the three is pharmacologically challenging, a point emphasized by molecular-simulation analyses that used NS-2359 as a model triple [2].
receptor fingerprint
()Reuptake inhibitor
transporter (NET)Reuptake inhibitor
transporter (SERT)Reuptake inhibitor
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
NS-2359 is an unapproved investigational compound sold for research use only (RUO); it is not a supplement and should not be self-administered. In controlled depression trials it produced more dry mouth, insomnia, anxiety, nausea, and tachycardia than placebo, with measurable increases in heart rate and blood pressure and higher dropout rates [1]. Its combined dopaminergic activity raises theoretical abuse-liability and cardiovascular considerations. No safe consumer dose has been established.
History
NS-2359 was discovered by the Danish company NeuroSearch and licensed to GlaxoSmithKline, which advanced it under the code GSK372475. Clinical development spanned major depressive disorder and additional indications during the 2000s. After the pivotal depression studies failed to show efficacy, development for that indication was discontinued [1].
Reputation
Among researchers, NS-2359 is remembered as one of the more thoroughly tested triple reuptake inhibitors and a cautionary example that the 'broad-spectrum monoamine' hypothesis did not deliver a superior antidepressant. It has occasional visibility in nootropic and research-chemical circles for its stimulant-like triple reuptake profile, but it carries no clinical endorsement and a documented tolerability burden [1].
Subjective profileweighing the evidence above
Nothing to salvage here. Two controlled trials found no antidepressant effect while it raised heart rate and blood pressure and drove more dropouts than placebo. Research use only, and not a stimulant substitute despite the balanced triple reuptake profile.
Resources
This entry is here for reference.
Research
- 1.Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials.
- 2.Understanding the Polypharmacological Profiles of Triple Reuptake Inhibitors by Molecular Simulation.
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is NS-2359 an effective antidepressant?
No. In two well-designed trials it did not outperform placebo, while standard antidepressants did. It is not approved for any use.
How is NS-2359 different from an SSRI?
An SSRI blocks only serotonin reuptake, whereas NS-2359 blocks serotonin, norepinephrine, and dopamine reuptake with roughly equal potency, giving it a more stimulant-like profile.
Adverse effects
- Dry mouth, insomnia, anxiety, nausea, and tachycardia occurred more often than placebo
- Increases in heart rate and blood pressure; no antidepressant efficacy demonstrated