Design, synthesis, and biological evaluation of novel diphenylmethyl-sulfinyl-bridged bisamides as wakefulness-promoting and anti-fatigue agents.

Narcolepsy severely impairs quality of life, characterized by irresistible sleepiness and persistent fatigue. The first-line agent modafinil (MOD) promotes wakefulness primarily by inhibiting the dopamine transporter (DAT), thereby elevating synaptic dopamine levels. In parallel, positive allosteric modulators (PAMs) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor enhance glutamatergic transmission, demonstrating notable wakefulness-promoting and anti-fatigue potential. Using MOD as a lead compound and leveraging the crystal structure of the AMPA receptor together with a homology model of the dopamine transporter (DAT), we designed, optimized and synthesized a series of diphenylmethyl-sulfinyl-bridged bisamide derivatives. Their activities were evaluated in vivo, identifying compound B1 as the most promising candidate. B1 significantly prolonged sleep latency and reduced sleep duration in pentobarbital-induced sleep models without increasing spontaneous locomotion. It also extended forced swimming time and rotarod endurance. Furthermore, B1 alleviated behavioral deficits from acute sleep deprivation. Preliminary mechanistic studies indicated that B1 exhibits moderate affinity for the dopamine transporter and enhances AMPA receptor-mediated ion currents while delaying channel deactivation, thereby functioning as a positive allosteric modulator. In summary, B1 is a novel and potent wakefulness-promoting and anti-fatigue candidate, supporting its further development as a therapeutic agent for narcolepsy and fatigue-related conditions.