TAK-653

TAK-653 is a synthetic small molecule that acts as a positive allosteric modulator, or potentiator, of AMPA-type glutamate receptors. Takeda scientists found it in a screen for potentiators with low agonist activity (Suzuki et al., 2023) and reported that it binds the receptor in a glutamate-dependent way with minimal agonist effect of its own (Suzuki et al., 2021). Its international nonproprietary name is osavampator.

Under the code NBI-1065845, Neurocrine Biosciences researchers described it in 2024 as an investigational compound in phase II development for major depressive disorder (Lin et al., 2024). A 2025 review reported that, as osavampator, it entered phase 3 placebo-controlled trials as an add-on in major depressive disorder in early 2025 (IsHak et al., 2025).

PubChem CID 56655833 matches the formula, weight and CAS number and supplies the structure and synonyms; PubMed records also pair TAK-653 with NBI-1065845 (Osaka and Kanazawa, 2023; Lin et al., 2024).

Published work on TAK-653 falls into five areas. Each summary below states the model used. Most cell and animal data come from Takeda's laboratories; published human data come from healthy volunteers, though a 2024 report notes a phase II study in adults with major depressive disorder (Lin et al., 2024).

How TAK-653 acts on AMPA receptors

Radiolabeled TAK-653 bound the receptor's ligand-binding domain in a glutamate-dependent manner. In CHO cells expressing human GluA1, it raised calcium influx only when glutamate was present, which the authors traced to structural interference at serine 743. In rat hippocampal neurons, 30 micromolar TAK-653 alone produced 1.7 percent of the current elicited by AMPA, against 39 percent for a comparison potentiator with strong agonist activity. In brain slices, it enhanced evoked AMPA receptor-mediated synaptic potentials more potently than AMPA or that comparison compound (Suzuki et al., 2021). Models: receptor protein, CHO cells, rat neurons and brain slices.

Memory and social behavior tests in animals

Given by mouth to rats, TAK-653 at 0.03 to 0.3 mg/kg raised the novelty discrimination index in novel object recognition, and at 0.1, 0.3, 3 and 10 mg/kg it reduced MK-801-induced working memory errors in a radial arm maze. In three male cynomolgus monkeys, 0.06 mg/kg raised delayed match-to-sample accuracy at a 16-second delay. In poly-I:C mice, a developmental immune activation model, 0.3 mg/kg raised a social approach score that was reduced in the model. The comparison potentiator affected only recognition memory, and AMPA affected neither (Suzuki et al., 2021). Models: rats, mice and monkeys.

Antidepressant-like effects in rats and monkeys

In rat cortical neurons, TAK-653 increased phosphorylated, active mTOR, p70S6 kinase, Akt and ERK and raised BDNF protein. In the rat reduction of submissive behavior model, six days of TAK-653 produced a significant antidepressant-like effect without the locomotor rise seen with ketamine (Hara et al., 2021).

An independent group put three male cynomolgus monkeys through 12 weeks of chronic unpredictable mild stress, then gave TAK-653 in food at 0.346 mg/kg daily for two weeks. Afterward the animals showed more motivation for food, less huddling and more movement, with lower plasma cortisol and IL-6 and higher BDNF, while IL-8 stayed raised (Li et al., 2025). Each monkey served as its own comparison. Models: rat neurons, rats and monkeys.

Convulsions and repeated exposure in rodents

The developers note that almost all known AMPA receptor potentiators carry a seizure risk (Suzuki et al., 2023). In their rat testing, TAK-653 caused convulsions in one animal 4 hours after 100 mg/kg by mouth. Against the exposure active in object recognition, they calculated margins of 419-fold for peak plasma concentration and 1,017-fold for total exposure, versus 3.4-fold and 4.0-fold for the comparison potentiator.

In mice, 14 days at 0.3 mg/kg left AMPA-induced hippocampal BDNF and Gadd45b mRNA unchanged, which the authors read as a low risk of receptor desensitization or sensitization (Suzuki et al., 2021). The healthy volunteer report notes partial seizures in primates, in unpublished Takeda data, at plasma levels well above those expected in that trial (Dijkstra et al., 2022). Models: rats and mice.

Pharmacology studies in healthy volunteers

One Takeda-sponsored crossover trial gave 24 healthy volunteers placebo or one of two single amounts. With transcranial magnetic stimulation, the higher amount increased motor-evoked potential amplitude without changing resting motor threshold or paired-pulse responses; in 31 rats, evoked motor responses rose from 0.3 mg/kg at similar plasma levels, and the compound was found in brain tissue (O'Donnell et al., 2021). On NeuroCart tests, neither amount changed body sway or subjective drug effects; the lower amount raised saccadic peak velocity and the higher amount raised adaptive tracking, a profile the authors called psychostimulant-like.

No serious adverse events, seizures or dissociative effects occurred; somnolence, headache and nasopharyngitis were most frequent (Dijkstra et al., 2022). In a later phase 1 study, repeated daily amounts of NBI-1065845 barely changed midazolam, ethinyl estradiol or levonorgestrel exposure (geometric mean ratios 0.87 to 1.01), and the authors concluded it is not a CYP3A inducer (Lin et al., 2024). Models: healthy adults and rats.