Bioisostere-Driven Discovery of SePP: A Selenium-Containing Polypharmacological Agent Relevant to Fragile X Syndrome

Diphenidine is a prototypical 1,2-diarylethylamine that functions as an uncompetitive <i>N</i>-methyl-d-aspartate receptor (NMDAR) antagonist and monoamine reuptake inhibitor. To examine the effects of phenyl-ring bioisosteric replacement within this scaffold, a series of diphenidine analogs incorporating chalcogen heterocycles (2-furan, 2-thiophene, 3-thiophene, and 2-selenophene) was synthesized. Compounds were evaluated for in vitro binding to rat forebrain NMDARs and inhibition of human DAT, NET, and SERT in cell-based assays, enabling assessment of polypharmacology. In silico analyses (molecular volume, tPSA, electrostatic surfaces, stockholder charges) and induced-fit docking were used to rationalize structure-activity relationships. The 2-selenophene analog SePP is notable given the underexplored role of selenium in medicinal chemistry. SePP exhibited favorable polypharmacology, good brain penetration in mouse pharmacokinetic studies, and prevented audiogenic seizures in <i>Fmr1</i> knockout mice (10 mg/kg, i.p.) without impairing motor coordination. These findings support further exploration of SePP for fragile X syndrome.