Design, synthesis, and biological evaluation of potent anti-fatigue compounds based on 1-BCP targeting the AMPA receptor

Fatigue is a prevalent issue in modern fast-paced lifestyles, exerting numerous adverse effects. Piperonylic acid piperidide (1-BCP), an α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulator, has demonstrated efficacy in alleviating sleep deprivation-induced fatigue. Furthermore, it significantly extends forced swimming time in mice and inhibits fatigue-induced changes in biochemical indices, validating its anti-fatigue effects. In this paper, a series of small-molecule compounds were designed with 1-BCP as the lead, from which the target compounds were screened by molecular dynamics simulation and molecular docking with the AMPA receptor. The target compounds were synthesised and evaluated for their anti-fatigue activity. The results of in vivo experiments showed that some compounds exhibited better anti-fatigue activity, among which compound A1 demonstrated the most significant activity, surpassing that of 1-BCP. The results of molecular dynamics simulation showed that A1 was able to bind to the AMPA receptor, preliminarily verifying the feasibility of the strategy for structural modification of 1-BCP. Taken together, A1 is a promising modulator of AMPA receptors. It is a potential candidate for further research on anti-fatigue drug development.