data + articles · 1 listed
newest 2007spec sheet7 rows
GlaxoSmithKline built GSK189254 out of a benzazepine chemical series distinct from the imidazole-based H3 antagonists that came before it, and it turned into one of the field's most cited cognition tool compounds. It binds human H3 receptors with subnanomolar affinity and more than 10,000-fold selectivity over other targets tested, and PET-style binding studies confirmed it engages H3 receptors directly in postmortem Alzheimer's disease brain tissue. In rodents it raised acetylcholine, noradrenaline, and dopamine release in the cortex and hippocampus and improved performance across passive avoidance, water maze, object recognition, and attentional set-shifting tasks, a strong enough preclinical package that GSK explored it for Alzheimer's-related cognitive symptoms; it never emerged as a named clinical program, and the compound is now used mainly as a research standard rather than a drug candidate.
- improved performance in passive avoidance, water maze, and object recognition tasks in rodents
- increased acetylcholine, noradrenaline, and dopamine release in cortex and hippocampus
- confirmed target engagement in human Alzheimer's disease brain tissue
- extremely high selectivity for H3 over other receptor targets
- GSK189254 binding was confirmed directly in postmortem Alzheimer's disease brain tissue, one of the few H3 tool compounds validated against real human pathology rather than rodent brain alone.
Mechanism
Selective H3 receptor with subnanomolar affinity for human H3 receptors, roughly 6- to 10-fold weaker at rodent H3, and greater than 10,000-fold selectivity over other targets tested; increases release of , noradrenaline, and in cortical and hippocampal circuits.
Safetyrisks and cautions, not medical advice
Contrary to the usual description of this compound as purely preclinical, GlaxoSmithKline did put it into people. A Phase II study gave it to 69 patients with narcolepsy and a Phase 1 crossover gave it to 40 healthy volunteers in a pain model, and a carbon-11 labeled version has been used as a brain imaging tracer in humans. The narcolepsy trial was stopped early on an interim futility test, meaning it was not working, not that it was hurting anyone. No adverse-event results from either study were ever posted, so what exists is proof of human exposure with no published account of how it was tolerated.
History
Discovered by GlaxoSmithKline in the mid-2000s from a novel benzazepine H3 antagonist series; characterized extensively in rodent cognition models and shown to bind H3 receptors directly in Alzheimer's disease brain tissue, but no public record shows it advancing into a named human clinical trial.
Resources
This entry is here for reference.
Research
1 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Did GSK189254 reach human trials?
There is no public record of it advancing into a named clinical trial; the published work is preclinical, including binding studies in postmortem human Alzheimer's brain tissue rather than living human dosing.
What made GSK189254 stand out from earlier H3 antagonists?
It came from a structurally distinct benzazepine series, had exceptionally high selectivity, and improved performance across an unusually broad range of cognition tests in rodents.
Limitations of the evidence
- no human clinical safety data on record
Notes and cautions
- rodent-to-human affinity differences complicate direct translation
- never progressed to a stage where tolerability in people was established