Novel Arylsulfonamide Derivatives with 5‑HT₆/5-HT₇ Receptor Antagonism Targeting Behavioral and Psychological Symptoms of Dementia

In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT_6/7/2A and D₂ receptors, without interacting with M₁ receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT_7/2A and D₂ receptors and weak interactions with key antitargets (M₁R and hERG) associated with side effects. Marked 5-HT₆ receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3–4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)­piperidin-1-yl]­butyl]­benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT₆ and D₂ receptors and negligible interactions at hERG and M₁ receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.