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AMPA receptor (GluA1/GluA2, ligand-binding domain)positive allosteric modulator; potentiates glutamate-evoked currents only when glutamate is present, with minimal intrinsic agonism

GluA1 Ser743 (structural interaction site)binds at the dimer interface and stabilizes the active conformation; structural interference at Ser743 is what keeps agonistic activity low

mTOR / p70S6K / Akt / ERK signaling (downstream)increases phosphorylation in cortical neurons secondary to AMPA-R activation

BDNF release (downstream)raises BDNF protein in rat primary cortical neurons and in a primate chronic-stress model

AMPA receptor (ionotropic glutamate receptor, GluA1-GluA4) ligand-binding domainPositive allosteric modulator; binds only in the presence of glutamate, at the intradimer interface in the channel-closed state, sterically gated by Ser750 in GluA2o (Ser743 in GluA1i)

Human GluA1 (flip) AMPA receptor, functional potentiationPotentiates glutamate-evoked Ca2+ influx in hGluA1i-expressing CHO cells; no effect without glutamate

Native neuronal AMPA receptor, Ca2+ influxPotentiates AMPA-evoked Ca2+ influx in rat primary hippocampal neurons

Native neuronal AMPA receptor, whole-cell currentPotentiates AMPA-elicited whole-cell currents in rat primary hippocampal neurons

AMPA receptor orthosteric (agonist) siteNo binding; TAK-653 does not displace [3H]-AMPA and instead mildly enhances its binding, confirming it is not an agonist

GluA1-GluA4 subunit selectivity (flip and flop, with TARP gamma-2)No prominent subunit selectivity across homomeric AMPA receptor subtypes

5-lipoxygenase (ALOX5)Off-target enzyme inhibition; the only hit in a 97-target screening panel at 10 uM

Akt/ERK to mTOR and p70S6 kinase signalling, and BDNF proteinDownstream consequence of AMPA receptor potentiation, not a binding target; increased phosphorylated mTOR, p70S6K, Akt and ERK and raised BDNF protein in rat primary cortical neurons

NMDA glycine siteactivates

CaMKII / PKCastimulates downstream

AMPA receptors (indirect)facilitates