Design, Synthesis, and Biological Evaluation of Potent Cognition-Improved Compounds Targeting AMPA Receptor Based on CX717

Aiming to develop safe and efficient cognitive enhancers, this study reports the design, synthesis, and biological evaluation of novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulators derived from the lead compound CX717. Twenty-four derivatives were designed, synthesized, and characterized by 1H-NMR, 13C-NMR, and high resolution MS (HR-MS). Molecular docking studies indicated that, compared to CX717, the compounds exhibited lower binding energy to the AMPA receptor. Cognition-improved activity was evaluated by passive avoidance, active avoidance, novel object recognition, and novel place recognition tests in mice. The results demonstrated that nine compounds significantly enhanced cognitive function in mice, with compounds B7 and C3 showing efficacy superior to CX717 in vivo. Furthermore, B7 and C3 alleviated serum oxidative stress, enhanced hippocampal glutamate transport efficiency, and reduced serum pro-inflammatory cytokine levels in scopolamine-treated mice. Subacute toxicity studies revealed favorable safety profiles for both compounds. Molecular dynamics simulations supported stable binding of B7 and C3 to the AMPA receptor, consistent with the structural modification strategy. Surface plasmon resonance (SPR) analysis demonstrated that B7 and C3 bound directly to the GluR2 protein with moderate affinity, with C3 showing higher affinity than B7. Patch-clamp experiments further showed that B7 and C3 positively modulated AMPA receptor–mediated currents, supporting their positive allosteric modulator (PAM)-like activity. The membrane permeability assay suggested that B7 and C3 had higher passive membrane permeability than CX717 in vitro. In conclusion, B7 and C3 demonstrated superior cognition-improved activity and safety compared to CX717, highlighting their potential as candidates for treating cognitive disorders.