Neuroscience Research Compound · For laboratory research use only
Also known as NBI-1065845
TAK-653 (9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c]1,2,4thiadiazine 2,2-dioxide) is a small-molecule positive allosteric modulator of the AMPA-type glutamate receptor discovered at Takeda. It is also designated NBI-1065845 in later clinical work7. Its originators describe it as an AMPA receptor potentiator with minimal agonistic activity, meaning that it enhances receptor responses to glutamate while producing little receptor activation on its own1,6.
Published research covers receptor pharmacology in recombinant cells, neurons and brain slices, rodent behavioural and safety models, a nonhuman primate chronic stress model, and phase 1 studies in healthy volunteers1,2,3,4,5,7.
As described in the research literature
As described in the research literature, TAK-653 bound to the ligand-binding domain of recombinant AMPA receptors in a glutamate-dependent manner and potentiated glutamate-induced calcium influx in cells expressing the GluA1 subunit, through structural interference at Ser7431. In primary neurons it augmented AMPA-induced calcium influx and currents with little agonistic effect, and in brain slices it enhanced electrically evoked AMPA receptor-mediated EPSPs1. An author correction to this paper was published in 2021.
In rat primary cortical neurons, TAK-653 was associated with increased phosphorylation of mTOR, p70S6 kinase, Akt and ERK, and with increased BDNF protein levels2. A review from the originating group discusses why low agonistic activity has been proposed to matter for AMPA receptor potentiators, in relation to bell-shaped response curves and seizure liability seen with earlier compounds6.
What published studies have examined
Binding, calcium influx and electrophysiology studies compared TAK-653 with AMPA itself and with LY451646, an AMPA receptor potentiator with prominent agonistic activity, in recombinant cells, primary neurons and brain slices1. The same work examined working and recognition memory tasks and the margin against convulsion in rats1.
The reduction of submissive behaviour model in rats was used to compare TAK-653 with ketamine, alongside locomotor activity as a behavioural index2. A chronic unpredictable mild stress model in monkeys examined behaviour and plasma cortisol, IL-6, IL-8 and BDNF5.
Single-pulse transcranial magnetic stimulation coupled with mechanomyography was used in rats to measure motor cortex excitability, with brain and plasma concentrations measured in parallel; the study also included a double-blind crossover arm in healthy volunteers using single and paired-pulse TMS3.
Sources [3]
A randomised, double-blind, placebo-controlled, three-way crossover study in 24 healthy volunteers used the NeuroCart battery of central nervous system tests as its pharmacodynamic measures4. A parallel-arm phase 1 study examined whether NBI-1065845 (TAK-653) induces cytochrome P450 3A, using the pharmacokinetics of midazolam and of an ethinyl estradiol-levonorgestrel combination as its measures7.
Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement.
Suzuki A, Kunugi A, Tajima Y, et al. Scientific Reports, 2021.
TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats.
Hara H, Suzuki A, Kunugi A, et al. Pharmacology, Biochemistry, and Behavior, 2021.
Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation.
O'Donnell P, Dijkstra FM, Damar U, et al. Translational Psychiatry, 2021.
Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers.
Dijkstra F, O'Donnell P, Klaassen E, et al. Translational Psychiatry, 2022.
TAK-653 Reverses Core Depressive Symptoms in Chronic Stress-Induced Monkey Model.
Li L, Zhang Z, Liu X, et al. Biomedicines, 2025.
Role of the AMPA receptor in antidepressant effects of ketamine and potential of AMPA receptor potentiators as a novel antidepressant.
Suzuki A, Hara H, Kimura H Neuropharmacology, 2023.
Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.
Lin S, Ionescu A, Maynard-Scott J, et al. Clinical and Translational Science, 2024.
This page is provided for research and educational reference only. It does not constitute medical advice, dosing guidance, or a recommendation for use. All compounds are strictly for laboratory and in-vitro research purposes.