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8R-Lisuride Is a Potent Stereospecific Histamine H₁-Receptor Partial Agonist

Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (R.A.B., T.t.L., T.B., O.P.Z., M.E., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., D.M.W., U.H., M.R.B.); and Departments of Pharmacology (M.R.B.) and Neurosciences and Psychiatry (D.M.W.), University of California at San Diego, San Diego, California

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-B 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.

Address correspondence to: R. A. Bakker, Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. E-mail: ra.bakker{at}few.vu.nl

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