Neuroscience Research Compound · For laboratory research use only
Also known as DMXBA
GTS-21 (DMXBA or DMXB-A; 3-(2,4-dimethoxybenzylidene)anabaseine) is a synthetic derivative of anabaseine, a nicotinic toxin found in marine animals2. It has been characterised as a selective partial agonist at alpha7 nicotinic acetylcholine receptors and, at rat receptors, also as a moderately potent antagonist at alpha4-beta2 receptors1,2.
Research has examined it in rodent cognition models, an auditory sensory gating model in DBA/2 mice, a transgenic Alzheimer's disease mouse model and in vitro inflammatory signalling in human and mouse immune cells1,3,4,5,6. It has also been evaluated in a phase 2 clinical trial in schizophrenia7.
As described in the research literature
As described in the research literature, DMXB activated alpha7 homo-oligomeric receptors expressed in Xenopus oocytes without significant activity at alpha2-, alpha3- or alpha4-containing subtypes1. A review by Kem noted that DMXBA is a much weaker partial agonist at human than at rat alpha7 receptors, while its 4-hydroxy metabolite shows good efficacy at both, so some observed effects may be due to this metabolite2.
Inflammatory signalling has been examined in several cell systems. In primary human leukocytes in vitro, GTS-21 inhibited pro-inflammatory cytokine release regardless of which Toll-like receptor was stimulated; the effect was not reversed by nicotinic antagonists but was abolished by the JAK2 inhibitor AG490, and involved JAK2-STAT3 activation at the transcriptional level5. A later study found that GTS-21 still suppressed LPS-induced IL-6 and TNF secretion in macrophages from mice lacking alpha7 receptors, indicating anti-inflammatory actions that are at least partly independent of the receptor6.
What published studies have examined
Receptor subtype selectivity was examined in Xenopus oocytes, and passive avoidance and Morris water task performance were studied in rats with bilateral nucleus basalis lesions, including whether the effects were sensitive to mecamylamine1. A review summarises behavioural studies in mice, rats, rabbits and monkeys and in vitro neuroprotection studies2.
In DBA/2 mice, which show a spontaneous deficit in inhibition of the hippocampal P20-N40 auditory evoked potential, the response to intragastric DMXB-A was recorded alone and with selective nicotinic antagonists; the effect was blocked by alpha-bungarotoxin but not by mecamylamine3.
Sources [3]
Primary rat microglia were used to examine amyloid-beta phagocytosis, and a transgenic Alzheimer's disease mouse model was used to measure brain amyloid-beta burden and memory. Gamma-secretase activity was measured in solubilised fractions of human neuroblastoma cells and transgenic mouse brain4.
Sources [4]
Cytokine release from human peripheral blood mononuclear cells, monocytes and whole blood was examined in vitro, with Toll-like receptor, CD14 and JAK2-STAT3 analyses5. NF-kappaB reporter cells and macrophages from wild-type and alpha7 knockout mice were used to test receptor dependence6.
A three-arm, two-site, double-blind, placebo-controlled crossover phase 2 trial in non-smoking participants with schizophrenia used the MATRICS Consensus Cognitive Battery to assess cognition, with negative symptom and psychiatric rating scales as clinical measures7.
Sources [7]
3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner.
Meyer EM, Tay ET, Papke RL, et al. Brain Research, 1997.
The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21).
Kem WR Behavioural Brain Research, 2000.
Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice.
Simosky JK, Stevens KE, Kem WR, et al. Biological Psychiatry, 2001.
Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Aβ accumulation through suppression of neuronal γ-secretase activity and promotion of microglial amyloid-β phagocytosis and ameliorates cognitive impairment in a mouse model of Alzheimer's disease.
Takata K, Amamiya T, Mizoguchi H, et al. Neurobiology of Aging, 2018.
GTS-21 inhibits pro-inflammatory cytokine release independent of the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation.
Kox M, van Velzen JF, Pompe JC, et al. Biochemical Pharmacology, 2009.
GTS-21 has cell-specific anti-inflammatory effects independent of α7 nicotinic acetylcholine receptors.
Garg BK, Loring RH PLoS One, 2019.
Initial phase 2 trial of a nicotinic agonist in schizophrenia.
Freedman R, Olincy A, Buchanan RW, et al. The American Journal of Psychiatry, 2008.
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