Structural Studies of the Dopamine D₄ Receptor Antagonist Sonepiprazole as an Inhibitor of Human Carbonic Anhydrases

In this study, we provide the first evidence that sonepiprazole, a dopamine D₄ receptor antagonist, acts as a potent inhibitor of human carbonic anhydrases (hCAs). Sonepiprazole exhibited significant inhibitory activity across the panel of catalytically active hCAs, with the exception of hCA IV, and hCA III. The most potent inhibition was observed against the brain-associated isoform hCA VII, with a <i>K</i> _I of 2.9 nM. Insights from X-ray crystallographic structures of the complexes with hCA I, hCA II, and hCA XII revealed that the sulfonamide group of sonepiprazole coordinates the zinc ion in the active site, a typical interaction for this class of inhibitors. Despite the presence of isoform-specific residues at the rim of the active site pocket, these variations seem not to significantly impact the compound overall inhibition potency. These findings highlight a dual functionality of sonepiprazole as both a D₄ receptor antagonist and a carbonic anhydrase inhibitor.