Spiro Hydantoins Can Reverse the Action of Positive Allosteric Modulators on GABAARs

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-09-30 DOI:10.1021/acsmedchemlett.5c00499

Dimosthenis A. Koinas, , , Xiaojuan Zhou, , , Karol S. Bruzik, , and , Keith W. Miller*,

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引用次数: 0

Abstract

GABA_ARs are the most abundant inhibitory neuroreceptors. Drugs that enhance their action are used to treat epilepsy, anxiety, and other conditions. Benzodiazepines can exert a range of allosteric interactions from positive to negative, but they only act on γ-subunit containing GABA_ARs. Agents acting in the transmembrane domain can interact with a wider range of GABA_ARs, but they exert only positive allosteric actions, and their therapeutic actions are often limited by sedation because their binding sites are the same as those used by general anesthetics. Consequently, their therapeutic action is limited by sedation. We report the synthesis and pharmacological evaluation of several novel spiro-hydantoins that do not modulate orthosteric agonist binding but do reverse the positive allosteric action of agents acting in the transmembrane domain. The reversal action occurs in the low micromolar range and is α-subunit dependent with action on α3β3γ2 receptors occurring at concentrations as low as 200 nM.

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Spiro Hydantoins可以逆转正变构调节剂对GABAARs的作用

GABAARs是最丰富的抑制性神经受体。增强其作用的药物用于治疗癫痫、焦虑和其他疾病。苯二氮卓类药物可以发挥一系列从正到负的变构相互作用，但它们只作用于含有γ-亚基的GABAARs。作用于跨膜区域的药物可以与更广泛的GABAARs相互作用，但它们只发挥积极的变构作用，并且它们的治疗作用通常受到镇静的限制，因为它们的结合位点与全身麻醉剂相同。因此，它们的治疗作用受到镇静的限制。我们报道了几种不调节正构激动剂结合但逆转跨膜域药物的正构变构作用的新型螺-羟肟酮的合成和药理学评价。逆转作用发生在低微摩尔范围内，并且是α-亚基依赖于α3β3γ2受体的作用，发生在低至200 nM的浓度下。

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.