Electrophysiological characterization of a novel AMPA receptor potentiator, TAK-137, in rat hippocampal neurons

Abstract

We have recently discovered an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) potentiator TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4] thiadiazine 2,2-dioxide with little agonistic effect. Under preclinical evaluation, TAK-137 demonstrated potent pro-cognitive effects with lower risks of seizure and bell-shaped dose response than LY451646, a potent AMPA-R potentiator, in rodents and monkeys. In this study, using rat primary cultured hippocampal neurons we explored the electrophysiological characterization of TAK-137 on native AMPA-Rs. TAK-137 dose-dependently enhanced AMPA-induced inward currents; its potency in the presence of AMPA was comparable to that of LY451646. The inward currents enhanced by TAK-137 were almost completely inhibited by GYKI53655, a selective AMPA-R blocker. Moreover, TAK-137 did not affect N-methyl-D-aspartate (NMDA)-activated inward currents, which suggests the AMPA-R-selective activation by TAK-137. In the absence of AMPA-R agonist, LY451646 at 30 μM induced slowly developing large inward currents, whereas TAK-137 at 30 μM exhibited a slight impact on baseline holding currents, further supporting the lower agonistic properties of TAK-137 than LY451646. Similar to LY451646, TAK-137 also increased the potency and binding affinity of AMPA for AMPA-Rs. These results indicate that TAK-137 is a highly potent and selective potentiator with little agonistic effect against native AMPA-Rs. Much greater agonistic effects of LY451646 than of TAK-137 may contribute to the increased risks of seizure and bell-shaped dose response in vivo.