data + articles · 2 listed
newest 2006spec sheet11 rows
SB-271046 is one of the first potent and selective serotonin 5-HT6 receptor antagonists, developed at SmithKline Beecham as a research tool and early cognition-enhancer candidate. It is a benzothiophene sulfonamide with high 5-HT6 affinity and behaves as an antagonist or inverse agonist at the receptor. Widely used in preclinical neuroscience, it helped establish the link between 5-HT6 blockade and increased cortical glutamate and cognitive performance. It was never developed into a marketed drug and remains a benchmark reference antagonist for the receptor.
- One of the first potent, selective 5-HT6 antagonists
- Established that 5-HT6 blockade raises frontal-cortex glutamate
- Behaves as an inverse agonist at constitutively active receptors
- Highly selective over other serotonin receptors
- Foundational reference tool for the entire 5-HT6 field
- Extensively validated in behavioural and neurochemical models
Overview
SB-271046 was among the earliest selective 5-HT6 receptor antagonists to emerge, developed at SmithKline Beecham initially with schizophrenia in mind and then, from the late 1990s, primarily as a cognition enhancer. It is a potent, selective antagonist with a reported pKi around 8.9, and its close analogue SB-258585 became a widely used radioligand for the receptor [1].
A key early finding, presented as the compound matured, was that administration of SB-271046 significantly increased glutamate and aspartate levels in the frontal cortex without altering noradrenaline, dopamine or serotonin, providing some of the first direct neurochemical evidence that 5-HT6 antagonism enhances excitatory transmission in a manner plausibly linked to cognition [1]. In receptor-efficacy studies that monitored the cAMP signaling pathway at constitutively active receptors, SB-271046 was reclassified as an inverse agonist rather than a neutral antagonist, producing negative efficacy well below basal signaling [2].
Although SB-271046 itself did not progress to a successful clinical product, it became a foundational pharmacological tool that shaped the entire 5-HT6 field, defining what selectivity and functional antagonism at the receptor look like and serving as the comparator against which many later agonists and antagonists were characterized [2]. It remains one of the most cited reference antagonists in 5-HT6 research.
- SB-271046 provided some of the first direct evidence that blocking 5-HT6 receptors raises glutamate in the frontal cortex, a neurochemical fingerprint later tied to the class's pro-cognitive effects.
- Its analogue SB-258585 became a standard radioligand used to measure 5-HT6 receptor occupancy in the brain.
Mechanism
SB-271046 is a selective competitive , and functionally an inverse , at the Gs-coupled 5-HT6 receptor. By suppressing both agonist-driven and constitutive 5-HT6 signaling on cortical interneurons it reduces inhibitory tone and increases frontal- release, which is thought to underlie its pro-cognitive activity in preclinical models. Its high selectivity over other receptors made it a clean tool for isolating 5-HT6-specific effects.
receptor fingerprint
5-HT6 receptorSelective antagonism / inverse agonism
Frontal- Increases extracellular glutamate and aspartate
Cortical interneuronsReduces 5-HT6 mediated inhibition
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
As a preclinical research compound, SB-271046 has no established human safety profile. In animal studies it was generally used without notable toxicity at behaviourally active doses, but it is not intended for human consumption and no clinical tolerability data support such use.
History
SB-271046 was developed at SmithKline Beecham (later GlaxoSmithKline) around the turn of the millennium, entering phase 1 testing by late 1999 as a candidate cognition enhancer for disorders including Alzheimer's disease and schizophrenia. It did not advance to a marketed product, but its rigorous characterization and the availability of the related radioligand SB-258585 cemented its role as a laboratory standard.
Reputation
In the neuroscience literature SB-271046 is regarded as a classic, foundational 5-HT6 antagonist, frequently chosen as the reference antagonist in mechanistic and behavioural studies. It has no standing as a consumer nootropic and is understood strictly as a research chemical.
Subjective profileweighing the evidence above
A reference tool, not a nootropic. It did its job by proving 5-HT6 blockade raises frontal-cortex glutamate and by anchoring an entire research field, but it never advanced toward a therapy and has no human safety or efficacy data. Read about it; do not buy it.
Resources
This entry is here for reference.
Research
- 1.SB-271046 (SmithKline Beecham)
- 2.Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
What is SB-271046 used for?
It is a laboratory research antagonist used to study the 5-HT6 receptor's role in cognition; it is not a medicine or consumer nootropic.
Is it an antagonist or an inverse agonist?
Both descriptions apply; it blocks agonist-driven signaling and also reduces the receptor's constitutive activity, making it a functional inverse agonist.
Why is it historically important?
It was one of the first selective 5-HT6 antagonists and helped show that blocking the receptor increases frontal-cortex glutamate, linking the target to cognition.
Was it ever a drug?
No. It entered early clinical testing but was never marketed; it endures as a reference research tool.
Can I take it as a nootropic?
No. There is no human safety data and it is intended solely for preclinical research.
Limitations of the evidence
- No human safety or efficacy data
- Never advanced to a marketed therapeutic
Notes and cautions
- Strictly a research chemical, not for consumption
- Preclinical dosing does not translate to human use