Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement

Atsushi Suzuki,Haruhide Kimura,Noriko Suzuki,Haruhiko Kuno,Yasukazu Tajima,Motohisa Suzuki,Masashi Toyofuku,Tomohiro Kaku,Akiyoshi Kunugi,Satoshi Sogabe,Yasuyuki Awasaki,Yohei Kosugi

doi:10.1038/s41598-021-93888-0

Abstract

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca2+ influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca2+ influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma Cmax) and 1017-fold (AUC plasma) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation.

Highlights

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects
We recently reported that structural interference at Ser[750] in AMPA-R GluA2o was key to lowering the agonistic effect of AMPA-R potentiators containing a dihydropyridothiadiazine 2,2-dioxides skeleton[16]
We previously reported that structural interference at Ser[750] in the channel-closed state of GluA2o LBD might be involved in the molecular mechanisms underlying the lower agonistic effect of AMPA-R potentiators with dihydropyridothiadiazine 2,2-dioxide derivatives and discovered TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (Fig. 1A)[16]

Summary

Introduction

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. AMPA-R potentiators such as LY451646 showed prominent agonistic effects (AMPA-R activation in the absence of agonist) in C a2+ influx assays and whole-cell current recordings using primary hippocampal neurons[16]. LY451646 had a narrow safety margin against seizures and a narrow bell-shaped dose-response for cognitive improvement in rats and monkeys[16]. TAK-137 bound to AMPA-R in a glutamate-dependent manner and showed a lower agonistic effect than LY451646 in both C a2+ influx assay and whole-cell patch clamp recording in rat primary hippocampal neurons. TAK-137 still maintained a weak agonistic effect[16,20]

Methods

Results

Conclusion