Synthesis and biological characterization of 4,4-difluoro-3(phenoxymethyl)piperidine scaffold as dopamine 4 receptor (D4R) antagonist in vitro tool compounds.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-05-29 DOI:10.1002/cmdc.202500298

Saeedeh Saeedi, Sumaiya Nahid, Anish Vadukoot, Corey R Hopkins

引用次数: 0

Abstract

We report the discovery and characterization of a novel series of 4,4-difluoropiperidine etherbased dopamine D4 receptor antagonists. Structure-activity relationship studies led to the identification of compound 14a, which displays exceptional binding affinity for the D4 receptor (Ki = 0.3 nM) and remarkable selectivity over other dopamine receptor subtypes (>2000-fold versus D1, D2, D3, and D5). However, compounds in this series were shown to have poor microsomal stability and high plasma protein binding. Despite these limitations, the exceptional selectivity profile of these compounds makes them valuable tool compounds for investigating D4 receptor signaling in cellular models of L-DOPA-induced dyskinesias. These findings provide important structural insights for the future development of metabolically stable D4 receptor antagonists for therapeutic applications.

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作为多巴胺4受体（D4R）拮抗剂的4,4-二氟-3（苯氧甲基）哌啶支架体外工具化合物的合成及生物学特性

我们报道了一种新型的4,4-二氟哌啶醚基多巴胺D4受体拮抗剂的发现和表征。结构-活性关系研究鉴定了化合物14a，该化合物对D4受体具有特殊的结合亲和力（Ki = 0.3 nM），对其他多巴胺受体亚型具有显著的选择性（比D1， D2， D3和D5高2000倍）。然而，该系列化合物具有较差的微粒体稳定性和较高的血浆蛋白结合。尽管存在这些局限性，但这些化合物的特殊选择性使它们成为研究左旋多巴诱导的运动障碍细胞模型中D4受体信号传导的有价值的工具化合物。这些发现为未来开发代谢稳定的D4受体拮抗剂的治疗应用提供了重要的结构见解。

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

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

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