8R-Lisuride Is a Potent Stereospecific Histamine H 1 -Receptor Partial Agonist

ABSTRACT The human histamine H 1 receptor (H 1 R) is an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are known to potently antagonize the H 1 R, thereby producing some of their side effects. In contrast, the tolerability and potential therapeutic utility of H 1 R agonism is currently unclear. We have used a cell-based functional assay to evaluate known therapeutics and reference drugs for H 1 R agonist activity. Our initial functional screen identified three ergot-based compounds possessing heretofore-unknown H 1 R 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-B with pEC 50 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 H 1 R yet reported. Investigation of the residues involved in histamine and lisuride binding, using H 1 R mutants and molecular modeling, have revealed that although these ligands are structurally different, the lisuride-binding pocket in the H 1 R closely corresponds to the histamine-binding pocket