The dopamine D2 receptors antagonist Veralipride inhibits carbonic anhydrases: solution and crystallographic insights on human isoforms

This study explores veralipride, a benzamide-class antipsychotic and dopamine D2 receptor antagonist, for its inhibitory effects on carbonic anhydrase (CA) isoforms. In vitro profiling reveals potent inhibition across hCA I, II, and CA XII. In addition, X-ray crystal structure experiments of veralipride adducts with hCA I, II, and CA XII mimic elucidates molecular interactions, aiding in designing polypharmacological compounds.

Abstract

The inhibitory effects of veralipride, a benzamide-class antipsychotic acting as dopamine D₂ receptors antagonist incorporates a primary sulfonamide moiety and was investigated for its interactions with carbonic anhydrase (CA) isoforms. In vitro profiling using the stopped-flow technique revealed that veralipride exhibited potent inhibitory activity across all tested hCA isoforms, with exception of hCA III. Comparative analysis with standard inhibitors, acetazolamide (AAZ), and sulpiride, provided insights for understanding the relative efficacy of veralipride as CA inhibitor. The study reports the X-ray crystal structure analysis of the veralipride adduct with three human (h) isoforms, hCA I, II, and CA XII mimic, allowing the understanding of the molecular interactions rationalizing its inhibitory effects against each isoform. These findings contribute to our understanding of veralipride pharmacological properties and for the design of structural analogs endowed with polypharmacological properties.

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