title: In vitro pharmacology of clinically used central nervous system-active drugs as inverse H(1) receptor agonists.
abstract: The human histamine H(1) receptor (H(1)R) is a prototypical G protein-coupled receptor and an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are also known to potently antagonize this receptor, underlying aspects of their side effect profiles. We have used the cell-based receptor selection and amplification technology assay to further define the clinical pharmacology of the human H(1)R by evaluating >130 therapeutic and reference drugs for functional receptor activity. Based on this screen, we have reported on the identification of 8R-lisuride as a potent stereospecific partial H(1)R agonist (Mol Pharmacol 65:538-549, 2004). In contrast, herein we report on a large number of varied clinical and chemical classes of drugs that are active in the central nervous system that display potent H(1)R inverse agonist activity. Absolute and rank order of functional potency of these clinically relevant brain-penetrating drugs may possibly be used to predict aspects of their clinical profiles, including propensity for sedation.
authors.affiliation: Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: Bakker
authors.forename: M W
authors.initials: MW
authors.lastname: Nicholas
authors.forename: T T
authors.initials: TT
authors.lastname: Smith
authors.forename: E S
authors.initials: ES
authors.lastname: Burstein
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
authors.forename: R
authors.initials: R
authors.lastname: Leurs
authors.forename: M R
authors.initials: MR
authors.lastname: Brann
authors.forename: D M
authors.initials: DM
authors.lastname: Weiner
mesh_terms: D000818:Animals; D019556:COS Cells; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017442:Histamine Agonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D011738:Pyrilamine / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects*
chemical_list: D002491:Central Nervous System Agents; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D008761:Methylhistamines; D011969:Receptors, Histamine H1; C069357:alpha-methylhistamine; D011738:Pyrilamine