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Rational design, synthesis, and pharmacological evaluation of a cohort of novel beta-adrenergic receptors ligands enables an assessment of structure-activity relationships
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-11-29 , DOI: 10.1016/j.ejmech.2022.114961
Jacopo Tricomi 1 , Luca Landini 2 , Valentina Nieddu 3 , Ugo Cavallaro 3 , Jillian G Baker 4 , Athanasios Papakyriakou 5 , Barbara Richichi 1
Affiliation  

Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key targets for a plethora of therapeutic interventions, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are useful as selective chemical tools in pharmacological studies of the three β-AR subtypes, or lead compounds for drug development is still a highly challenging task. This is mainly due to the intrinsic plasticity of β-ARs as G protein-coupled receptors in conjunction with the requirement for functional receptor subtype selectivity, tissue specificity and minimal off-target effects. With the aim to provide insight into structure-activity relationships for the three β-AR subtypes, we have synthesized and obtained the pharmacological profile of a series of structurally diverse compounds (named MC) that were designed based on the aryloxy-propanolamine scaffold of SR59230A. Comparative analysis of their predicted binding mode within the active and inactive states of the receptors in combination with their pharmacological profile revealed key structural elements that control their activity as agonists or antagonists, in addition to clues about substituents that mediate selectivity for one receptor subtype over the others. We anticipate that these results will facilitate selective β-AR drug development efforts.



中文翻译:

一组新型 β-肾上腺素能受体配体的合理设计、合成和药理学评估能够评估结构-活性关系

在过去十年中,能够调节 β-肾上腺素能信号的分子的生物医学应用变得越来越有吸引力,表明 β-肾上腺素能受体 (β-ARs) 是包括癌症在内的多种治疗干预的关键靶点。尽管在 β-AR 药物发现方面取得了成功,但鉴定可用作三种 β-AR 亚型药理学研究中的选择性化学工具的 β-AR 配体或用于药物开发的先导化合物仍然是一项极具挑战性的任务。这主要是由于 β-AR 作为 G 蛋白偶联受体的内在可塑性,以及对功能性受体亚型选择性、组织特异性和最小脱靶效应的要求。为了深入了解三种 β-AR 亚型的构效关系,MC ) 是基于 SR59230A 的芳氧基丙醇胺支架设计的。对它们在受体活性和非活性状态下的预测结合模式及其药理学特征的比较分析揭示了控制它们作为激动剂或拮抗剂活性的关键结构元素,此外还有关于介导一种受体亚型选择性的取代基的线索其他。我们预计这些结果将促进选择性 β-AR 药物的开发工作。

更新日期:2022-11-29
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