RT Journal Article SR Electronic T1 8R-Lisuride Is a Potent Stereospecific Histamine H1-Receptor Partial Agonist JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 538 OP 549 DO 10.1124/mol.65.3.538 VO 65 IS 3 A1 R. A. Bakker A1 D. M. Weiner A1 T. ter Laak A1 T. Beuming A1 O. P. Zuiderveld A1 M. Edelbroek A1 U. Hacksell A1 H. Timmerman A1 M. R. Brann A1 R. Leurs YR 2004 UL http://molpharm.aspetjournals.org/content/65/3/538.abstract AB 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-κB 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.