Multifunctional Arylsulfone and Arylsulfonamide-Based Ligands with Prominent Mood-Modulating Activity and Benign Safety Profile, Targeting Neuropsychiatric Symptoms of Dementia

The current pharmaceutical
market lacks therapeutic agents designed
to modulate behavioral disturbances associated with dementia. To address
this unmet medical need, we designed multifunctional ligands characterized
by a nanomolar affinity for clinically relevant targets that are associated
with the disease pathology, namely, the 5-HT2A/6/7 and
D2 receptors. Compounds that exhibited favorable functional
efficacy, water solubility, and metabolic stability were selected
for more detailed study. Pharmacological profiling revealed that compound 11 exerted pronounced antidepressant activity (MED 0.1 mg/kg),
outperforming commonly available antidepressant drugs, while compound 16 elicited a robust anxiolytic activity (MED 1 mg/kg), exceeding
comparator anxiolytics. In contrast to the existing psychotropic agents
tested, the novel chemotypes did not negatively impact cognition.
At a chronic dose regimen (25 days), 11 did not induce
significant metabolic or adverse blood pressure disturbances. These
promising therapeutic-like activities and benign safety profiles make
the novel chemotypes potential treatment options for dementia patients.