Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland; Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, 30-348, Krakow, Poland.
University of Parma, Department of Medicine and Surgery, Via Gramsci 14, 43126, Parma, Italy.
Eur J Pharmacol. 2021 Jan 5;890:173611. doi: 10.1016/j.ejphar.2020.173611. Epub 2020 Oct 2.
Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery.
组胺是一种多功能的生物胺，对四种不同的组胺受体具有亲和力。现有的药理学研究表明，组胺 H 受体配体在治疗许多炎症和免疫调节疾病方面具有有用性，包括过敏性鼻炎、哮喘、特应性皮炎、结肠炎或瘙痒。迄今为止，已经开发了几种有效的组胺 H 受体配体，但尚未有任何一种被注册为药物。在这项研究中，一系列有效的吲哚样和三嗪衍生物在组胺 H 受体的放射性配体置换和功能测定中，以及在人嗜酸性粒细胞与内皮细胞黏附中进行了测试。对选定的化合物进行了通透性、细胞毒性、代谢和体内研究。黏附测定将不同组化合物的活性与已知对组胺 H 受体的亲和力区分开来。大多数测试的化合物都下调了黏附细胞的数量。然而，黏附测定揭示了测试化合物的其他性质，这些性质在放射性配体置换和基于水母发光蛋白的功能测定中没有被检测到。此外，对于一些测试的化合物，这些异常作用在体内研究中得到了证实。总之，嗜酸性粒细胞黏附测定揭示了组胺 H 受体配体的药理学活性，随后在体内得到了证实，这突显了基于细胞的表型筛选方法在药物发现中的价值。
