molecules of the month

The Takeda AMPA-R potentiator, TAK-653, is a glutamate-dependent potentiator that exhibits minimal agonism. AMPA-R agonism is associated with seizure risk and bell-shaped dose-response effects. As reviewer Jake Schwarz notes, companies including Cortex Pharmaceuticals (now RespireRx) and Lilly have been trying to develop AMPA modulators for decades, testing both “low-impact” AMPA modulators with a wider therapeutic window but lower potency and “high-impact” compounds with a narrow therapeutic window but higher potency. The Takeda team was able to identify compounds with a wide safety margin against convulsion (400-1000x), behaving like “low-impact” modulators, but with significant efficacy and potency to enable a 6 mg oral dose. They suggest that selectively enhancing AMPA-R activation by physiological glutamate is key to enhancing cognition, as nonselective activation of resting…