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

## TL;DR

Scientists discovered a new selenium-based compound, SePP, that shows potential for treating Fragile X Syndrome by affecting multiple brain targets.

## Contribution

The novel contribution is the discovery of SePP, a selenium-containing compound with polypharmacological activity relevant to Fragile X Syndrome.

## Key findings

- SePP showed favorable polypharmacology and good brain penetration in mouse studies.
- SePP prevented audiogenic seizures in Fmr1 knockout mice without affecting motor coordination.
- In silico analyses helped explain the structure–activity relationships of SePP and related compounds.

## Abstract

Diphenidine is a prototypical 1,2-diarylethylamine that
functions
as an uncompetitive N-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 Fmr1 knockout mice (10 mg/kg,
i.p.) without impairing motor coordination. These findings support
further exploration of SePP for fragile X syndrome.