TAK-653

2022-07-31: Nootropics reference:

TAK-653 #

• High impact AMPAkines induce a Gq-protein coupled endoplasmic calcium release in cortical neurons: a possible mechanism for explaining the toxicity of high impact AMPAkines

• 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 (Sep 2022)
  • Improves Stroop test (proxy of Executive Function apparently): TAK-653 0.5 mg but not 6 mg decreased the number of correct responses in incongruent trials
  • demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex.
    • TAK-653 (6mg) increased SPV by 15.5 to 19.5 deg/s, which is larger than caffeine 60 mg (11.6 deg/s) and dexamphetamine 20 mg (12.7 deg/s), but smaller than modafinil 200 mg (24.6 deg/s). Increases in smooth pursuit eye movements represented only roughly one-third of those induced by methylphenidate
    • Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation
• [Pharmacokinetic and pharmacodynamic properties of the investigational AMPA receptor positive allosteric modulator TAK-653 after single and multiple rising doses in healthy volunteers]
  • Tried 0.3-18mg.
  • Maximum plasma concentrations were attained within 1.25 h to 5 h after dosing, the terminal half-life varied from 33.1 h to 47.8 h and cerebrospinal fluid concentrations were suggestive of rapid brain penetration
• Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement (Suzuki et al. 15 July 2021)
  • Did not show prominent subunit selectivity for homomeric AMPA-R
  • 3 and 10mg/kg in mice. The former had like a 20% greater effect on BDNF release after AMPA treatment.
  • In monkeys, the beneficial effect (~20%) on “delayed match-to-sample” task was maintained for 24 hours after administration. Its half life is 9.4 $\pm$ 3.8 hours at 0.03 mg/kg p.o in monkeys.
  • Enhanced sustained attention in poor-performing mice. Increased novel objection recognition test results by like 10%. 0.03-0.3 mg/kg were all pretty similar.
  • Ameliorated abnormal social interaction in models of schizophrenia (poly-I:C. No idea, but it made them complete antisocial and then back to near baseline)
  • 10 μM in prefrontal cortex had the best effect on AMPAR-mediated EPSPs in the PFC: tripling EPSP duration and 6x the number of spikes.
• TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats (Dec 2021)
  • 0.1 or 1 mg/kg p.o. The time to reach peak plasma concentration after the oral administration of TAK-653 at 1 mg/kg was between 1 and 2 h
  • “Increased” phosphorylated and active forms of mTOR, P70S6, and AKT and ERK.
  • Stimulated mTOR and BDNF production.
  • News to me that Ketamine activates AMPAR and increases BDNF production.
  • Despite expectations, no relevant clinical effects have been demonstrated for the CX series.
  • In vitro for 10 minutes wih 1μM tripled ERK phosphorylation. Nothing tooo crazy otherwise
  • Virtually no agonist activity. Steric repulsion by GluR2 Ser750 of the closed AMPAR caused TAK-653 only to bind in the presence of a ligand.
    • Otherwise, there would be some kind of bell-shaped dose-response curve whereby excess glutamate release could get you in big trouble.
    • GluR2 Ser750 == GluR1 Ser743.
• Novel AMPA Receptor Potentiators TAK-137 and TAK-653 as Potential Rapid-Acting Antidepressants (2021)

Dose #

• So for me personally, 2.5 mg might be the sweet spot.

Intranasal #

• More and more stores are coming out the woodwork stocking it in powder form…
  • 1g/$300 ($0.3/mg) or 250mg/$100 ($0.4/mg) on PGLchem. Awesome deal.
    • They also sell $80 200mg (0.4/mg) bottles in PEG.
  • 1g/$500 + shipping from Sirsad. (Compare to $0.49/mg on EC)
• Blank says even 1mg intranasal feels more potent than 4 mg oral. He apparently didn’t respond too well even to high doses orally. He says low dose IN/oral feels about the same, but oral megadose is floaty while IN megadose makes you attack problems