Bakker R A, Weiner D M, ter Laak T, Beuming T, Zuiderveld O P, Edelbroek M, Hacksell U, Timmerman H, Brann M R, Leurs R
Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Mol Pharmacol. 2004 Mar;65(3):538-49. doi: 10.1124/mol.65.3.538.
The human histamine H1 receptor (H1R) is an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are known to potently antagonize the H1R, thereby producing some of their side effects. In contrast, the tolerability and potential therapeutic utility of H1R agonism is currently unclear. We have used a cell-based functional assay to evaluate known therapeutics and reference drugs for H1R agonist activity. Our initial functional screen identified three ergot-based compounds possessing heretofore-unknown H1R agonist activity. 8R-lisuride demonstrated potent agonist activity in various assays including receptor selection and amplification technology, inositol phosphate accumulation, and activation of nuclear factor-kappaB with pEC50 values of 8.1, 7.9, and 7.9, respectively, and with varying degrees of efficacy. Based on these assays, 8R-lisuride is the most potent stereospecific partial agonist for the human H1R yet reported. Investigation of the residues involved in histamine and lisuride binding, using H1R mutants and molecular modeling, have revealed that although these ligands are structurally different, the lisuride-binding pocket in the H1R closely corresponds to the histamine-binding pocket. The discovery of a potent stereospecific partial H1R agonist provides a valuable tool to further characterize this important therapeutic target in vitro.
人类组胺H1受体（H1R）是开发用于治疗过敏疾病的拮抗剂的一个重要且特征明确的靶点。已知许多神经精神药物能有效拮抗H1R，从而产生一些副作用。相比之下，H1R激动作用的耐受性和潜在治疗效用目前尚不清楚。我们使用了一种基于细胞的功能测定法来评估已知治疗药物和参考药物的H1R激动剂活性。我们最初的功能筛选鉴定出三种基于麦角的化合物具有此前未知的H1R激动剂活性。8R-利苏瑞ide在包括受体选择和扩增技术、肌醇磷酸积累以及核因子κB激活等各种测定中均表现出强效激动剂活性，其pEC50值分别为8.1、7.9和7.9，且具有不同程度的效力。基于这些测定，8R-利苏瑞ide是迄今报道的对人类H1R最有效的立体特异性部分激动剂。利用H1R突变体和分子建模对参与组胺和利苏瑞ide结合的残基进行研究后发现，尽管这些配体在结构上不同，但H1R中的利苏瑞ide结合口袋与组胺结合口袋密切对应。一种强效立体特异性部分H1R激动剂的发现为在体外进一步表征这一重要治疗靶点提供了一种有价值的工具。
