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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-02-10 eCollection Date: 2025-03-13 DOI:10.1021/acsmedchemlett.5c00034

Andrea Angeli, Marta Ferraroni, Clemente Capasso, Claudiu T Supuran

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Abstract

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 K _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.

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多巴胺D4受体拮抗剂索奈哌唑作为人碳酸酐酶抑制剂的结构研究。

在这项研究中，我们首次提供了多巴胺D4受体拮抗剂索奈哌唑作为人类碳酸酐酶（hCAs）有效抑制剂的证据。索奈哌唑在所有具有催化活性的hCA中均表现出显著的抑制活性，但hCA IV和hCA III除外。最有效的抑制作用是对脑相关亚型hCA VII的抑制，其ki为2.9 nM。与hCA I、hCA II和hCA XII配合物的x射线晶体结构揭示索奈哌唑的磺胺基与活性位点的锌离子配位，这是该类抑制剂的典型相互作用。尽管在活性位点口袋边缘存在异构体特异性残基，但这些变化似乎不会显著影响化合物的整体抑制效力。这些发现突出了索奈哌唑作为D4受体拮抗剂和碳酸酐酶抑制剂的双重功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.