Abstract：
β-adrenergic receptors (βARs) belong to a key molecular targets that regulate the most important processes occurring in the human organism. Although over the last decades a zebrafish model has been developed as a model complementary to rodents in biomedical research, the role of β2AR in regulation of pathological and toxicological effects remains to elucidate. Therefore, the study aimed to clarify the role of β2AR with a particular emphasis on the distinct role of subtypes A and B of zebrafish β2AR. As model compounds selective β2AR agonists - (R,R)-fenoterol ((R,R)-Fen) and its new derivatives: (R,R)-4\'-methoxyfenoterol ((R,R)-MFen) and (R,R)-4\'-methoxy-1-naphtylfenoterol ((R,R)-MNFen) - were tested. We described dose-dependent changes observed after fenoterols exposure in terms of general toxicity, cardiotoxicity and neurobehavioural responses. Subsequently, to better characterise the role of β2-adrenergic stimulation in zebrafish, we have performed a series of molecular docking simulations. Our results indicate that (R,R)-Fen displays the highest affinity for subtype A of zebrafish β2AR and β2AAR might be involved in pigment depletion. (R,R)-MFen shows the lowest affinity for zebrafish β2ARs out of the tested fenoterols and this might be associated with its cardiotoxic and anxiogenic effects. (R,R)-MNFen displays the highest affinity for subtype B of zebrafish β2AR and modulation of this receptor might be associated with the development of malformations, increases locomotor activity and induces a negative chronotropic effect. Taken together, the presented data offer insights into the functional responses of the zebrafish β2ARs confirming their intraspecies conservation, and support the translation of the zebrafish model in pharmacological and toxicological research.
摘要：
β-肾上腺素能受体（βARs）属于调节人类生物体中最重要过程的关键分子靶标。尽管在过去的几十年中，斑马鱼模型已被开发为生物医学研究中啮齿动物的补充模型，β2AR在调节病理和毒理学效应中的作用仍有待阐明。因此,该研究旨在阐明β2AR的作用，特别强调斑马鱼β2AR亚型A和B的不同作用。作为模型化合物的选择性β2AR激动剂-（R，R)-非诺特罗((R,R)-Fen)及其新衍生物:(R,R)-4'-甲氧基非诺特罗((R，R)-MFen)和(R,R)-4'-甲氧基-1-萘基非诺特罗((R,R)-MNFen)-被测试。我们描述了非诺特罗暴露后在一般毒性方面观察到的剂量依赖性变化，心脏毒性和神经行为反应。随后，为了更好地表征β2-肾上腺素能刺激在斑马鱼中的作用，我们进行了一系列的分子对接模拟。我们的结果表明(R，R）-Fen对斑马鱼β2AR的亚型A具有最高的亲和力，β2AAR可能参与色素消耗。(R,在测试的非诺特罗中，R）-MFen对斑马鱼β2AR的亲和力最低，这可能与其心脏毒性和焦虑作用有关。(R,R)-MNFen对斑马鱼β2AR的B亚型具有最高的亲和力,该受体的调节可能与畸形的发生有关,增加运动活动并诱导负向变时效应。一起来看,提供的数据提供了对斑马鱼β2AR的功能反应的见解，证实了它们的种内保守性，并支持斑马鱼模型在药理和毒理学研究中的翻译。
